Evaluating Parametrization Protocols for Hydration Free Energy Calculations with the AMOEBA Polarizable Force FieldClick to copy article linkArticle link copied!
Abstract
Hydration free energy (HFE) calculations are often used to assess the performance of biomolecular force fields and the quality of assigned parameters. The AMOEBA polarizable force field moves beyond traditional pairwise additive models of electrostatics and may be expected to improve upon predictions of thermodynamic quantities such as HFEs over and above fixed-point-charge models. The recent SAMPL4 challenge evaluated the AMOEBA polarizable force field in this regard but showed substantially worse results than those using the fixed-point-charge GAFF model. Starting with a set of automatically generated AMOEBA parameters for the SAMPL4 data set, we evaluate the cumulative effects of a series of incremental improvements in parametrization protocol, including both solute and solvent model changes. Ultimately, the optimized AMOEBA parameters give a set of results that are not statistically significantly different from those of GAFF in terms of signed and unsigned error metrics. This allows us to propose a number of guidelines for new molecule parameter derivation with AMOEBA, which we expect to have benefits for a range of biomolecular simulation applications such as protein–ligand binding studies.
Introduction
AMOEBA Potential

Methods
Data Set
Parametrization Protocols
Figure 1
Figure 1. General AMOEBA parametrization protocol. An initial solute conformer is geometry optimized and subject to distributed multipole analysis to extract a set of atomic multipoles. Multipole parameters are refined by fitting to the molecular electrostatic potential of single or multiple solute conformations. Valence, vdW, and polarizability parameters are assigned based on atom type, while other parameters (e.g., polarization groups) may be assigned either automatically or manually by inspection.
set | name | modified dihedrals | modified polarization groups | multipole conformational fit | QM ESP basis set | water model | empirical multipole scaling |
---|---|---|---|---|---|---|---|
1 | Poltype | yes | no | single | 6-311++G(2d,2p) | wat03 | Poltypea |
2 | new polgps | yes | yes | single | 6-311++G(2d,2p) | wat03 | Poltypea |
3 | multifit | yes | yes | multiple | 6-311++G(2d,2p) | wat03 | none |
4 | Aug-cc-pvtz | yes | yes | multiple | aug-cc-pVTZ | wat03 | none |
5 | Wat14 | yes | yes | multiple | aug-cc-pVTZ | wat14 | none |
6 | OH scaled | yes | yes | multiple | aug-cc-pVTZ | wat14 | aliphatic OH |
7 | GAFF | N/A | N/A | N/A | N/A | TIP3P | N/A |
Poltype performed automatic scaling of hydroxyl (OH) and amine (NHn) quadrupole values of functional groups beyond simply the aliphatic OH groups suggested by Shi et al. (see Text S1). The effects of this additional empirical scaling are not directly evaluated here.
Simulation Protocol

Figure 2
Figure 2. Thermodynamic cycle used in performing alchemical free energy calculations. The cycle has four defined end points: (a) a fully interacting solute in vacuum, (b) a fully interacting solute in water, (c) a discharged and vdW decoupled solute in vacuum, and (d) a discharged and vdW decoupled solute in water. Simulations were separated into three legs: alchemical discharging and vdW decoupling steps in solution, and a discharging step in vacuum. The overall ΔGhyd was calculated as ΔGdischarging,vac – ΔGdecoupling,sol – ΔGdischarging,sol.
Statistical Analysis
Results and Discussion
Improvement of Poltype Parameters
Figure 3
Figure 3. Plot of predicted against experimental HFE for parameter set 1. AMOEBA solute parameters were derived using Poltype (38) with modifications outlined in the Supporting Information. Error bars are modeled as standard deviations across three repeat simulations. Solutes 25 and 42 (labeled) had large associated uncertainties due to sampling differences between runs.
set | name | MSE (kcal mol–1) | MUE (kcal mol–1) | R2 | Kendall τ |
---|---|---|---|---|---|
1 | Poltype | 0.484 ≤ 1.032 ≤ 1.616 | 1.553 ≤ 1.850 ≤ 2.289 | 0.50 ≤ 0.75 ≤ 0.93 | 0.43 ≤ 0.62 ≤ 0.73 |
2 | new polgps | 0.590 ≤ 1.125 ≤ 1.687 | 1.538 ≤ 1.838 ≤ 2.284 | 0.51 ≤ 0.77 ≤ 0.93 | 0.46 ≤ 0.63 ≤ 0.75 |
3 | multifit | 0.375 ≤ 1.007 ≤ 1.605 | 1.391 ≤ 1.765 ≤ 2.322 | 0.56 ≤ 0.80 ≤ 0.95 | 0.49 ≤ 0.67 ≤ 0.77 |
4 | Aug-cc-pvtz | 0.634 ≤ 1.218 ≤ 1.761 | 1.410 ≤ 1.774 ≤ 2.265 | 0.59 ≤ 0.82 ≤ 0.96 | 0.51 ≤ 0.69 ≤ 0.78 |
5 | Wat14 | –0.489 ≤ 0.226 ≤ 0.828 | 1.262 ≤ 1.616 ≤ 2.232 | 0.62 ≤ 0.84 ≤ 0.96 | 0.46 ≤ 0.65 ≤ 0.75 |
6 | OH scaled | 0.000 ≤ 0.530 ≤ 1.071 | 1.240 ≤ 1.529 ≤ 1.955 | 0.63 ≤ 0.84 ≤ 0.96 | 0.47 ≤ 0.66 ≤ 0.76 |
7 | GAFF | –0.184 ≤ 0.202 ≤ 0.674 | 0.873 ≤ 1.100 ≤ 1.470 | 0.74 ≤ 0.86 ≤ 0.90 | 0.58 ≤ 0.73 ≤ 0.84 |
Upper and lower bounds for each metric are 95% CI estimates.
Figure 4
Figure 4. Example of possible polarization group definitions for solute L05 (1,2-dimethoxybenzene). A careful choice of polarization groups (right) allows a more realistic response of induced polarization to changes in molecular conformation, e.g., rotation of the two methoxy substituents.
Figure 5
Figure 5. Comparison of parameter sets 1 (blue) and 2 (red) for the subset of substituted benzene solutes. Error bars modeled as standard deviations across three repeat simulations. In set 2, new polarization groups were assigned manually where necessary for each molecule in the subset. Precise polarization groups are detailed in Figure S2.
set | name | MSE (kcal mol–1) | MUE (kcal mol–1) | R2 | Kendall τ |
---|---|---|---|---|---|
1 | Poltype | –0.501 ≤ 0.463 ≤ 1.149 | 1.064 ≤ 1.391 ≤ 1.839 | 0.25 ≤ 0.71 ≤ 0.93 | 0.08 ≤ 0.56 ≤ 0.86 |
2 | new polgps | 0.007 ≤ 0.799 ≤ 1.364 | 0.989 ≤ 1.347 ≤ 1.664 | 0.30 ≤ 0.75 ≤ 0.93 | 0.32 ≤ 0.72 ≤ 0.92 |
Upper and lower bounds for each metric are 95% CI estimates.
Improvement of Manual Parametrization
Figure 6
Figure 6. Comparison of mean molecular ESP around substituted benzene solutes calculated with QM and with AMOEBA parameter sets 2 and 3. Fifty solute structures were extracted from each MD simulation at λ = 1.0, geometry optimized, and subject to QM and AMOEBA ESP calculations. Each point corresponds to a single MD structure, but multiple structures may optimize to similar QM geometries, resulting in irregular horizontal clustering of points. Generating multipoles using a multiconformational fit (parameter set 3, black) results in a much more accurate recreation of QM ESP for conformations visited during a simulation (R2 = 0.97) than a single conformational fit (parameter set 2, blue, and R2 = 0.44).
Statistical Comparison
Figure 7
Figure 7. Comparison of predicted and experimental ΔGhyd for all parameter sets and accompanying linear regressions.
comparison set | ||||||||
---|---|---|---|---|---|---|---|---|
reference set | metric | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
1 | MSE | N/A | 0.3275 | 0.9101 | 0.3671 | 0.0050 | 0.0255 | 0.0386 |
1 | MUE | N/A | 0.7537 | 0.2854 | 0.4982 | 0.0884 | 0.1054 | 0.0001 |
7 | MSE | 0.0386 | 0.0198 | 0.0879 | 0.0238 | 0.9595 | 0.3956 | N/A |
7 | MUE | 0.0001 | 0.0003 | 0.0040 | 0.0056 | 0.0904 | 0.2236 | N/A |
Significant differences are highlighted in bold. Tests between MSE distributions use paired Student’s t-tests, and those between MUE distributions used Wilcoxon signed-rank tests.
Conclusions
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jctc.6b00276.
Full details of AMOEBA parametrization choices and methods for each parameter set, all SAMPL4 solute structures and details of manually defined solute polarization groups, comparison of solute RMSD between parameter sets 2 and 3, definitions of solute subgroups, statistical p values for the ANOVA test between solute HFE predictions with different methods, and a summary of pairwise significant differences between solute results across parameter sets are available (PDF)
Terms & Conditions
Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.
Acknowledgment
Calculations in this work made use of the Iridis3 and Iridis4 supercomputers at the University of Southampton. We thank all members of the EPSRC-NSF funded SI2 consortium, particularly Jay Ponder, Teresa Head-Gordon, Martin Head-Gordon, David Case, Jason Swails, Chris-Kriton Skylaris, Mark Tuckerman, Paul Nerenberg, Lorna Smith, and Ilian Todorov, for helpful discussions throughout.
AM1-BCC | AM1-bond charge correction |
AMOEBA | atomic multipole optimized energetics for biomolecular applications |
ANOVA | analysis of variance |
CI | confidence interval |
DMA | distributed multipole analysis |
ESP | electrostatic potential |
GAFF | general Amber force field |
HFE | hydration free energy |
HSD | honest significant difference |
MD | molecular dynamics |
MSE | mean signed error |
MUE | mean unsigned error |
QM | quantum mechanics |
RESP | restrained electrostatic potential |
RMSD | root mean square deviation |
SAMPL | statistical assessment for modeling of proteins and ligands |
SMARTS | Smiles arbitrary target specification |
vdW | van der Waals |
References
This article references 82 other publications.
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- 2Nicholls, A.; Mobley, D. L.; Guthrie, J. P.; Chodera, J. D.; Bayly, C. I.; Cooper, M. D.; Pande, V. S. Predicting Small-Molecule Solvation Free Energies: An Informal Blind Test for Computational Chemistry J. Med. Chem. 2008, 51 (4) 769– 779 DOI: 10.1021/jm070549+Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXps1GqsQ%253D%253D&md5=6d882cf6dfedacaf4df4204c58a0598ePredicting Small-Molecule Solvation Free Energies: An Informal Blind Test for Computational ChemistryNicholls, Anthony; Mobley, David L.; Guthrie, J. Peter; Chodera, John D.; Pande, Vijay S.Journal of Medicinal Chemistry (2008), 51 (4), 769-779CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Exptl. data on the transfer of small mols. between vacuum and water are relatively sparse. This makes it difficult to assess whether computational methods are truly predictive of this important quantity or merely good at explaining what has been seen. To explore this, a prospective test was performed of two different methods for estg. solvation free energies: an implicit solvent approach based on the Poisson-Boltzmann equation and an explicit solvent approach using alchem. free energy calcns. For a set of 17 small mols., root mean square errors from expt. were between 1.3 and 2.6 kcal/mol, with the explicit solvent free energy approach yielding somewhat greater accuracy but at greater computational expense. Insights from outliers and suggestions for future prospective challenges of this kind are presented.
- 3Shivakumar, D.; Williams, J.; Wu, Y.; Damm, W.; Shelley, J.; Sherman, W. Prediction of Absolute Solvation Free Energies Using Molecular Dynamics Free Energy Perturbation and the OPLS Force Field J. Chem. Theory Comput. 2010, 6 (5) 1509– 1519 DOI: 10.1021/ct900587bGoogle Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXkslKhu7g%253D&md5=25d464fb9238e3235e881945c0b50a76Prediction of Absolute Solvation Free Energies using Molecular Dynamics Free Energy Perturbation and the OPLS Force FieldShivakumar, Devleena; Williams, Joshua; Wu, Yujie; Damm, Wolfgang; Shelley, John; Sherman, WoodyJournal of Chemical Theory and Computation (2010), 6 (5), 1509-1519CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)The accurate prediction of protein-ligand binding free energies is a primary objective in computer-aided drug design. The solvation free energy of a small mol. provides a surrogate to the desolvation of the ligand in the thermodn. process of protein-ligand binding. Here, we use explicit solvent mol. dynamics free energy perturbation to predict the abs. solvation free energies of a set of 239 small mols., spanning diverse chem. functional groups commonly found in drugs and drug-like mols. We also compare the performance of abs. solvation free energies obtained using the OPLS_2005 force field with two other commonly used small mol. force fields - general AMBER force field (GAFF) with AM1-BCC charges and CHARMm-MSI with CHelpG charges. Using the OPLS_2005 force field, we obtain high correlation with exptl. solvation free energies (R2 = 0.94) and low av. unsigned errors for a majority of the functional groups compared to AM1-BCC/GAFF or CHelpG/CHARMm-MSI. However, OPLS_2005 has errors of over 1.3 kcal/mol for certain classes of polar compds. We show that predictions on these compd. classes can be improved by using a semiempirical charge assignment method with an implicit bond charge correction.
- 4Martins, S. A.; Sousa, S. F.; Ramos, M. J.; Fernandes, P. A. Prediction of Solvation Free Energies with Thermodynamic Integration Using the General Amber Force Field J. Chem. Theory Comput. 2014, 10 (8) 3570– 3577 DOI: 10.1021/ct500346yGoogle Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFyqsL7K&md5=6387491d131a18d6e883151f6cc92089Prediction of Solvation Free Energies with Thermodynamic Integration Using the General Amber Force FieldMartins, Silvia A.; Sousa, Sergio F.; Ramos, Maria Joao; Fernandes, Pedro A.Journal of Chemical Theory and Computation (2014), 10 (8), 3570-3577CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)Computer-aided drug design (CADD) techniques can be very effective in reducing costs and speeding up drug discovery. The detn. of binding and solvation free energies is pivotal for this process and is, therefore, the subject of many studies. In this work, the solvation free energy change (ΔΔGsolv) for a total of 92 transformations in small mols. was predicted using Thermodn. Integration (TI). The aim was to compare exptl. and calcd. solvation free energies for typical and prime addns. considered in drug optimizations, analyzing trends, and optimizing a TI protocol. The results showed a good agreement between exptl. and predicted values, with an overestimation of the predicted values for CH3, halogens, and NH2, as well as an underestimation for CONH2, but all fall within ±1 kcal/mol. NO2 addn. showed a larger and systematic underestimation of the predicted ΔΔGsolv, indicating the need for special attention in these cases. For small mols., if no exptl. data is available, using TI as a theor. strategy thus appears to be a suitable choice in CADD. It provides a good compromise between time and accuracy.
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- 6Jorgensen, W. L. The Many Roles of Computation in Drug Discovery Science 2004, 303 (5665) 1813– 1818 DOI: 10.1126/science.1096361Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXitFehu7w%253D&md5=77b2fac63e750ca7cdc7e4f35654549aThe Many Roles of Computation in Drug DiscoveryJorgensen, William L.Science (Washington, DC, United States) (2004), 303 (5665), 1813-1818CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)A review. An overview is given on the diverse uses of computational chem. in drug discovery. Particular emphasis is placed on virtual screening, de novo design, evaluation of drug-likeness, and advanced methods for detg. protein-ligand binding.
- 7Kelly, C. P.; Cramer, C. J.; Truhlar, D. G. SM6: A Density Functional Theory Continuum Solvation Model for Calculating Aqueous Solvation Free Energies of Neutrals, Ions, and Solute–Water Clusters J. Chem. Theory Comput. 2005, 1 (6) 1133– 1152 DOI: 10.1021/ct050164bGoogle Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFegsrbE&md5=7be83d42a3375786978c86eb50600f0eSM6: A Density Functional Theory Continuum Solvation Model for Calculating Aqueous Solvation Free Energies of Neutrals, Ions, and Solute-Water ClustersKelly, Casey P.; Cramer, Christopher J.; Truhlar, Donald G.Journal of Chemical Theory and Computation (2005), 1 (6), 1133-1152CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)A new charge model, called Charge Model 4 (CM4), and a new continuum solvent model, called Solvation Model 6 (SM6), are presented. Using a database of aq. solvation free energies for 273 neutrals, 112 ions, and 31 ion-water clusters, parameter sets for the mPW0 hybrid d. functional of Adamo and Barone (Adamo, C.; Barone, V. J. Chem. Phys. 1998, 108, 664-675) were optimized for use with the following four basis sets: MIDI!6D, 6-31G(d), 6-31+G(d), and 6-31+G(d,p). SM6 separates the observable aq. solvation free energy into two different components: one arising from long-range bulk electrostatic effects and a second from short-range interactions between the solute and solvent mols. in the first solvation shell. This partition of the observable solvation free energy allows SM6 to effectively model a wide range of solutes. For the 273 neutral solutes in the test set, SM6 achieves an av. error of ∼0.50 kcal/mol in the aq. solvation free energies. For solutes, esp. ions, that have highly concd. regions of charge d., adding an explicit water mol. to the calcn. significantly improves the performance of SM6 for predicting solvation free energies. The performance of SM6 was tested against several other continuum models, including SM5.43R and several different implementations of the Polarizable Continuum Model (PCM). For both neutral and ionic solutes, SM6 outperforms all of the models against which it was tested. Also, SM6 is the only model (except for one with an av. error 3.4 times larger) that improves when an explicit solvent mol. is added to solutes with concd. charge densities. Thus, in SM6, unlike the other continuum models tested here, adding one or more explicit solvent mol. to the calcn. is an effective strategy for improving the prediction of the aq. solvation free energies of solutes with strong local solute-solvent interactions. This is important, because local solute-solvent interactions are not specifically accounted for by bulk electrostatics, but modeling these interactions correctly is important for predicting the aq. solvation free energies of certain solutes. Finally, SM6 retains its accuracy when used in conjunction with the B3LYP and B3PW91 functionals, and in fact the solvation parameters obtained with a given basis set may be used with any good d. functional or fraction of Hartree-Fock exchange.
- 8Marenich, A. V.; Olson, R. M.; Kelly, C. P.; Cramer, C. J.; Truhlar, D. G. Self-Consistent Reaction Field Model for Aqueous and Nonaqueous Solutions Based on Accurate Polarized Partial Charges J. Chem. Theory Comput. 2007, 3 (6) 2011– 2033 DOI: 10.1021/ct7001418Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFSqsrbJ&md5=002518393e08359394f671a73ca9a548Self-Consistent Reaction Field Model for Aqueous and Nonaqueous Solutions Based on Accurate Polarized Partial ChargesMarenich, Aleksandr V.; Olson, Ryan M.; Kelly, Casey P.; Cramer, Christopher J.; Truhlar, Donald G.Journal of Chemical Theory and Computation (2007), 3 (6), 2011-2033CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)A new universal continuum solvation model (where "universal" denotes applicable to all solvents), called SM8, is presented. It is an implicit solvation model, also called a continuum solvation model, and it improves on earlier SMx universal solvation models by including free energies of solvation of ions in nonaq. media in the parametrization. SM8 is applicable to any charged or uncharged solute composed of H, C, N, O, F, Si, P, S, Cl, and/or Br in any solvent or liq. medium for which a few key descriptors are known, in particular dielec. const., refractive index, bulk surface tension, and acidity and basicity parameters. It does not require the user to assign mol.-mechanics types to an atom or group; all parameters are unique and continuous functions of geometry. It may be used with any level of electronic structure theory as long as accurate partial charges can be computed for that level of theory; the authors recommend using it with self-consistently polarized Charge Model 4 or other self-consistently polarized class IV charges, in which case analytic gradients are available. The model separates the observable solvation free energy into two components: the long-range bulk electrostatic contribution arising from a self-consistent reaction field treatment using the generalized Born approxn. for electrostatics is augmented by the non-bulk-electrostatic contribution arising from short-range interactions between the solute and solvent mols. in the first solvation shell. The cavities for the bulk electrostatics calcn. are defined by superpositions of nuclear-centered spheres whose sizes are detd. by intrinsic at. Coulomb radii. The radii used for aq. soln. are the same as parametrized previously for the SM6 aq. solvation model, and the radii for nonaq. soln. are parametrized by a training set of 220 bare ions and 21 clustered ions in acetonitrile, methanol, and DMSO. The non-bulk-electrostatic terms are proportional to the solvent-accessible surface areas of the atoms of the solute and have been parametrized using solvation free energies for a training set of 2346 solvation free energies for 318 neutral solutes in 90 nonaq. solvents and water and 143 transfer free energies for 93 neutral solutes between water and 15 org. solvents. The model is tested with three d. functionals and with four basis sets: 6-31+G(d,p), 6-31+G(d), 6-31G(d), and MIDI!6D. The SM8 model achieves mean unsigned errors of 0.5-0.8 kcal/mol in the solvation free energies of tested neutrals and mean unsigned errors of 2.2-7.0 kcal/mol for ions. The model outperforms the earlier SM5.43R and SM7 universal solvation models as well as the default Polarizable Continuum Model (PCM) implemented in Gaussian 98/03, the Conductor-like PCM as implemented in GAMESS, Jaguar's continuum model based on numerical soln. of the Poisson equation, and the GCOSMO model implemented in NWChem.
- 9Mobley, D. L.; Guthrie, J. P. FreeSolv: A Database of Experimental and Calculated Hydration Free Energies, with Input Files J. Comput.-Aided Mol. Des. 2014, 28 (7) 711– 720 DOI: 10.1007/s10822-014-9747-xGoogle Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXpvVeitb0%253D&md5=23d3152ee50654206bac75a6e4492101FreeSolv: a database of experimental and calculated hydration free energies, with input filesMobley, David L.; Guthrie, J. PeterJournal of Computer-Aided Molecular Design (2014), 28 (7), 711-720CODEN: JCADEQ; ISSN:0920-654X. (Springer)This work provides a curated database of exptl. and calcd. hydration free energies for small neutral mols. in water, along with mol. structures, input files, refs., and annotations. We call this the Free Solvation Database, or FreeSolv. Exptl. values were taken from prior literature and will continue to be curated, with updated exptl. refs. and data added as they become available. Calcd. values are based on alchem. free energy calcns. using mol. dynamics simulations. These used the GAFF small mol. force field in TIP3P water with AM1-BCC charges. Values were calcd. with the GROMACS simulation package, with full details given in refs. cited within the database itself. This database builds in part on a previous, 504-mol. database contg. similar information. However, addnl. curation of both exptl. data and calcd. values has been done here, and the total no. of mols. is now up to 643. Addnl. information is now included in the database, such as SMILES strings, PubChem compd. IDs, accurate ref. DOIs, and others. One version of the database is provided in the Supporting Information of this article, but as ongoing updates are envisioned, the database is now versioned and hosted online. In addn. to providing the database, this work describes its construction process. The database is available free-of-charge via http://www.escholarship.org/uc/item/6sd403pz.
- 10Guthrie, J. P. A Blind Challenge for Computational Solvation Free Energies: Introduction and Overview J. Phys. Chem. B 2009, 113 (14) 4501– 4507 DOI: 10.1021/jp806724uGoogle Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjslelsLo%253D&md5=3a14054823eaed5775309d268173f59dA Blind Challenge for Computational Solvation Free Energies: Introduction and OverviewGuthrie, J. PeterJournal of Physical Chemistry B (2009), 113 (14), 4501-4507CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)A review. The accompanying set of papers arose from a recent blind challenge to computational solvation energies. The challenge was based on a set of 63 drug-like mols. for which solvation energies could be extd. from the literature. While the results are encouraging, there is still need for improvement.
- 11Geballe, M. T.; Skillman, A. G.; Nicholls, A.; Guthrie, J. P.; Taylor, P. J. The SAMPL2 Blind Prediction Challenge: Introduction and Overview J. Comput.-Aided Mol. Des. 2010, 24 (4) 259– 279 DOI: 10.1007/s10822-010-9350-8Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmsFSmsb8%253D&md5=bab4eefa9886bf8b06c6f3cd02e9acd1The SAMPL2 blind prediction challenge: introduction and overviewGeballe, Matthew T.; Skillman, A. Geoffrey; Nicholls, Anthony; Guthrie, J. Peter; Taylor, Peter J.Journal of Computer-Aided Molecular Design (2010), 24 (4), 259-279CODEN: JCADEQ; ISSN:0920-654X. (Springer)A review. The interactions between a mol. and the aq. environment underpin any process that occurs in soln., from simple chem. reactions to protein-ligand binding to protein aggregation. Fundamental measures of the interaction between mol. and aq. phase, such as the transfer energy between gas phase and water or the energetic difference between two tautomers of a mol. in soln., remain nontrivial to predict accurately using current computational methods. SAMPL2 represents the third annual blind prediction of transfer energies, and the first time tautomer ratios were included in the challenge. Over 60 sets of predictions were submitted, and each participant also attempted to est. the error in their predictions, a task that proved difficult for most. The results of this blind assessment of the state of the field for transfer energy and tautomer ratio prediction both indicate where the field is performing well and point out flaws in current methods.
- 12Geballe, M. T.; Guthrie, J. P. The SAMPL3 Blind Prediction Challenge: Transfer Energy Overview J. Comput.-Aided Mol. Des. 2012, 26 (5) 489– 496 DOI: 10.1007/s10822-012-9568-8Google ScholarThere is no corresponding record for this reference.
- 13Guthrie, J. P. SAMPL4, a Blind Challenge for Computational Solvation Free Energies: The Compounds Considered J. Comput.-Aided Mol. Des. 2014, 28 (3) 151– 168 DOI: 10.1007/s10822-014-9738-yGoogle ScholarThere is no corresponding record for this reference.
- 14Mobley, D.; Wymer, K.; Lim, N.; Guthrie, J. P. Blind Prediction of Solvation Free Energies from the SAMPL4 Challenge J. Comput.-Aided Mol. Des. 2014, 28 (3) 135– 150 DOI: 10.1007/s10822-014-9718-2Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjvVyqu74%253D&md5=4b67de6fdc5fa04d58d10e3d5a1692e5Blind prediction of solvation free energies from the SAMPL4 challengeMobley, David L.; Wymer, Karisa L.; Lim, Nathan M.; Guthrie, J. PeterJournal of Computer-Aided Molecular Design (2014), 28 (3), 135-150CODEN: JCADEQ; ISSN:0920-654X. (Springer)Here, we give an overview of the small mol. hydration portion of the SAMPL4 challenge, which focused on predicting hydration free energies for a series of 47 small mols. These gas-to-water transfer free energies have in the past proven a valuable test of a variety of computational methods and force fields. Here, in contrast to some previous SAMPL challenges, we find a relatively wide range of methods perform quite well on this test set, with RMS errors in the 1.2 kcal/mol range for several of the best performing methods. Top-performers included a quantum mech. approach with continuum solvent models and functional group corrections, alchem. mol. dynamics simulations with a classical all-atom force field, and a single-conformation Poisson-Boltzmann approach. While 1.2 kcal/mol is still a significant error, exptl. hydration free energies covered a range of nearly 20 kcal/mol, so methods typically showed substantial predictive power. Here, a substantial new focus was on evaluation of error ests., as predicting when a computational prediction is reliable vs. unreliable has considerable practical value. We found, however, that in many cases errors are substantially underestimated, and that typically little effort has been invested in estg. likely error. We believe this is an important area for further research.
- 15SAMPL5 https://drugdesigndata.org/about/sampl5 (accessed Dec 16, 2015) .Google ScholarThere is no corresponding record for this reference.
- 16Ponder, J. W.; Wu, C. J.; Ren, P. Y.; Pande, V. S.; Chodera, J. D.; Schnieders, M. J.; Haque, I.; Mobley, D. L.; Lambrecht, D. S.; DiStasio, R. A.; Head-Gordon, M.; Clark, G. N. I.; Johnson, M. E.; Head-Gordon, T. Current Status of the AMOEBA Polarizable Force Field J. Phys. Chem. B 2010, 114 (8) 2549– 2564 DOI: 10.1021/jp910674dGoogle Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1Gmt7s%253D&md5=c2a2addabc2e6d3f2dc4b4db878bd282Current Status of the AMOEBA Polarizable Force FieldPonder, Jay W.; Wu, Chuanjie; Ren, Pengyu; Pande, Vijay S.; Chodera, John D.; Schnieders, Michael J.; Haque, Imran; Mobley, David L.; Lambrecht, Daniel S.; Di Stasio, Robert A.; Head-Gordon, Martin; Clark, Gary N. I.; Johnson, Margaret E.; Head-Gordon, TeresaJournal of Physical Chemistry B (2010), 114 (8), 2549-2564CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)A review. Mol. force fields have been approaching a generational transition over the past several years, moving away from well-established and well-tuned, but intrinsically limited, fixed point charge models toward more intricate and expensive polarizable models that should allow more accurate description of mol. properties. The recently introduced AMOEBA force field is a leading publicly available example of this next generation of theor. model, but to date, it has only received relatively limited validation, which we address here. We show that the AMOEBA force field is in fact a significant improvement over fixed charge models for small mol. structural and thermodn. observables in particular, although further fine-tuning is necessary to describe solvation free energies of drug-like small mols., dynamical properties away from ambient conditions, and possible improvements in arom. interactions. State of the art electronic structure calcns. reveal generally very good agreement with AMOEBA for demanding problems such as relative conformational energies of the alanine tetrapeptide and isomers of water sulfate complexes. AMOEBA is shown to be esp. successful on protein-ligand binding and computational X-ray crystallog. where polarization and accurate electrostatics are crit.
- 17Demerdash, O.; Yap, E.-H.; Head-Gordon, T. Advanced Potential Energy Surfaces for Condensed Phase Simulation Annu. Rev. Phys. Chem. 2014, 65 (1) 149– 174 DOI: 10.1146/annurev-physchem-040412-110040Google ScholarThere is no corresponding record for this reference.
- 18Shi, Y.; Ren, P.; Schnieders, M.; Piquemal, J.-P. Polarizable Force Fields for Biomolecular Modeling. In Reviews in Computational Chemistry; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2015; Vol. 28, pp 51– 86.Google ScholarThere is no corresponding record for this reference.
- 19Huang, J.; Lopes, P. E. M.; Roux, B.; MacKerell, A. D. Recent Advances in Polarizable Force Fields for Macromolecules: Microsecond Simulations of Proteins Using the Classical Drude Oscillator Model J. Phys. Chem. Lett. 2014, 5 (18) 3144– 3150 DOI: 10.1021/jz501315hGoogle Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVeksLbO&md5=4ed2a9179936991094aaa597e80b2a61Recent advances in polarizable force fields for macromolecules: Microsecond simulations of proteins using the classical Drude oscillator modelHuang, Jing; Lopes, Pedro E. M.; Roux, Benoit; MacKerell, Alexander D.Journal of Physical Chemistry Letters (2014), 5 (18), 3144-3150CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)A review. The authors summarize recent efforts to include the explicit treatment of induced electronic polarization in biomol. force fields. Methods used to treat polarizability, including the induced dipole, fluctuating charge, and classical Drude oscillator models, are presented, including recent advances in force fields using those methods. This is followed by recent results obtained with the Drude model, including microsecond mol. dynamics (MD) simulations of multiple proteins in explicit solvent. The results show significant variability of backbone and side-chain dipole moments as a function of environment, including significant changes during individual simulations. Dipole moments of water in the vicinity of the proteins reveal small but systematic changes, with the direction of the changes dependent on the environment. Analyses of the full proteins show that the polarizable Drude model leads to larger values of the dielec. const. of the protein interior, esp. in the case of hydrophobic regions. These results indicate that the inclusion of explicit electronic polarizability leads to significant differences in the phys. forces affecting the structure and dynamics of proteins, which can be investigated in a computationally tractable fashion in the context of the Drude model.
- 20Baker, C. M. Polarizable Force Fields for Molecular Dynamics Simulations of Biomolecules Wiley Interdiscip. Rev. Comput. Mol. Sci. 2015, 5 (2) 241– 254 DOI: 10.1002/wcms.1215Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXisF2nu7s%253D&md5=acffeab784e0876f9641f0874d87020fPolarizable force fields for molecular dynamics simulations of biomoleculesBaker, Christopher M.Wiley Interdisciplinary Reviews: Computational Molecular Science (2015), 5 (2), 241-254CODEN: WIRCAH; ISSN:1759-0884. (Wiley-Blackwell)Mol. dynamics simulations are well established for the study of biomol. systems. Within these simulations, energy functions known as force fields are used to det. the forces acting on atoms and mols. While these force fields have been very successful, they contain a no. of approxns., included to overcome limitations in computing power. One of the most important of these approxns. is the omission of polarizability, the process by which the charge distribution in a mol. changes in response to its environment. Since polarizability is known to be important in many biochem. situations, and since advances in computer hardware have reduced the need for approxns. within force fields, there is major interest in the use of force fields that include an explicit representation of polarizability. As such, a no. of polarizable force fields have been under development: these have been largely exptl., and their use restricted to specialized researchers. This situation is now changing. Parameters for fully optimized polarizable force fields are being published, and assocd. code incorporated into std. simulation software. Simulations on the hundred-nanosecond timescale are being reported, and are now within reach of all simulation scientists. In this overview, I examine the polarizable force fields available for the simulation of biomols., the systems to which they have been applied, and the benefits and challenges that polarizability can bring. In considering future directions for development of polarizable force fields, I examine lessons learnt from non-polarizable force fields, and highlight issues that remain to be addressed. WIREs Comput Mol Sci 2015, 5:241-254. doi: 10.1002/wcms.1215. Conflict of interest: The author has declared no conflicts of interest for this article.
- 21Ren, P. Y.; Wu, C.; Ponder, J. W. Polarizable Atomic Multipole-Based Molecular Mechanics for Organic Molecules J. Chem. Theory Comput. 2011, 7 (10) 3143– 3161 DOI: 10.1021/ct200304dGoogle Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFGgtrbN&md5=04b55d33dfd8770899a5d2300c9b6cf9Polarizable Atomic Multipole-Based Molecular Mechanics for Organic MoleculesRen, Pengyu; Wu, Chuanjie; Ponder, Jay W.Journal of Chemical Theory and Computation (2011), 7 (10), 3143-3161CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)An empirical potential based on permanent at. multipoles and at. induced dipoles is reported for alkanes, alcs., amines, sulfides, aldehydes, carboxylic acids, amides, aroms., and other small org. mols. Permanent at. multipole moments through quadrupole moments were derived from gas phase ab initio MO calcns. The van der Waals parameters are obtained by fitting to gas phase homodimer QM energies and structures, as well as exptl. densities and heats of vaporization of neat liqs. As a validation, the hydrogen bonding energies and structures of gas phase heterodimers with water are evaluated using the resulting potential. For 32 homo- and heterodimers, the assocn. energy agrees with ab initio results to within 0.4 kcal/mol. The root-mean-square deviation of the hydrogen bond distance from QM optimized geometry is <0.06 Å. Liq. self-diffusion and static dielec. consts. computed from a mol. dynamics simulation are consistent with exptl. values. The force field is also used to compute the solvation free energy of 27 compds. not included in the parametrization process, with a root-mean-square error of 0.69 kcal/mol. The results obtained in this study suggest that the AMOEBA force field performs well across different environments and phases. The key algorithms involved in the electrostatic model and a protocol for developing parameters are detailed to facilitate extension to addnl. mol. systems.
- 22Baker, C. M.; Lopes, P. E. M.; Zhu, X.; Roux, B.; Mackerell, A. D. Accurate Calculation of Hydration Free Energies Using Pair-Specific Lennard-Jones Parameters in the CHARMM Drude Polarizable Force Field J. Chem. Theory Comput. 2010, 6 (4) 1181– 1198 DOI: 10.1021/ct9005773Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXisFGmsbY%253D&md5=2118f6899e5328a95e08bd4e41411a2fAccurate Calculation of Hydration Free Energies using Pair-Specific Lennard-Jones Parameters in the CHARMM Drude Polarizable Force FieldBaker, Christopher M.; Lopes, Pedro E. M.; Zhu, Xiao; Roux, Benoit; MacKerell, Alexander D.Journal of Chemical Theory and Computation (2010), 6 (4), 1181-1198CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)Lennard-Jones (LJ) parameters for a variety of model compds. have previously been optimized within the CHARMM Drude polarizable force field to reproduce accurately pure liq. phase thermodn. properties as well as addnl. target data. While the polarizable force field resulting from this optimization procedure has been shown to satisfactorily reproduce a wide range of exptl. ref. data across numerous series of small mols., a slight but systematic overestimate of the hydration free energies has also been noted. Here, the reprodn. of exptl. hydration free energies is greatly improved by the introduction of pair-specific LJ parameters between solute heavy atoms and water oxygen atoms that override the std. LJ parameters obtained from combining rules. The changes are small and a systematic protocol is developed for the optimization of pair-specific LJ parameters and applied to the development of pair-specific LJ parameters for alkanes, alcs., and ethers. The resulting parameters not only yield hydration free energies in good agreement with exptl. values, but also provide a framework upon which other pair-specific LJ parameters can be added as new compds. are parametrized within the CHARMM Drude polarizable force field. Detailed anal. of the contributions to the hydration free energies reveals that the dispersion interaction is the main source of the systematic errors in the hydration free energies. This information suggests that the systematic error may result from problems with the LJ combining rules and is combined with anal. of the pair-specific LJ parameters obtained in this work to identify a preliminary improved combining rule.
- 23Zhong, Y.; Patel, S. Nonadditive Empirical Force Fields for Short-Chain Linear Alcohols: Methanol to Butanol. Hydration Free Energetics and Kirkwood-Buff Analysis Using Charge Equilibration Models J. Phys. Chem. B 2010, 114 (34) 11076– 11092 DOI: 10.1021/jp101597rGoogle ScholarThere is no corresponding record for this reference.
- 24Zhang, J.; Yang, W.; Piquemal, J.-P.; Ren, P. Modeling Structural Coordination and Ligand Binding in Zinc Proteins with a Polarizable Potential J. Chem. Theory Comput. 2012, 8 (4) 1314– 1324 DOI: 10.1021/ct200812yGoogle Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XitFKkt7g%253D&md5=d96c6b59f1ab977b69dda9f57d31b54aModeling Structural Coordination and Ligand Binding in Zinc Proteins with a Polarizable PotentialZhang, Jiajing; Yang, Wei; Piquemal, Jean-Philip; Ren, PengyuJournal of Chemical Theory and Computation (2012), 8 (4), 1314-1324CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)As the second most abundant cation in the human body, zinc is vital for the structures and functions of many proteins. Zinc-contg. matrix metalloproteinases (MMPs) have been widely investigated as potential drug targets in a range of diseases ranging from cardiovascular disorders to cancers. However, it remains a challenge in theor. studies to treat zinc in proteins with classical mechanics. In this study, we examd. Zn2+ coordination with org. compds. and protein side chains using a polarizable at. multipole-based electrostatic model. We find that the polarization effect plays a detg. role in Zn2+ coordination geometry in both matrix metalloproteinase (MMP) complexes and zinc-finger proteins. In addn., the relative binding free energies of selected inhibitors binding with MMP13 have been estd. and compared with exptl. results. While not directly interacting with the small mol. inhibitors, the permanent and polarizing field of Zn2+ exerts a strong influence on the relative affinities of the ligands. The simulation results also reveal that the polarization effect on binding is ligand-dependent and thus difficult to incorporate into fixed-charge models implicitly.
- 25Fried, S. D.; Wang, L.-P.; Boxer, S. G.; Ren, P.; Pande, V. S. Calculations of the Electric Fields in Liquid Solutions J. Phys. Chem. B 2013, 117 (50) 16236– 16248 DOI: 10.1021/jp410720yGoogle Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvV2ku7%252FO&md5=6d31f2009947b9792643f3abaafe5a60Calculations of the Electric Fields in Liquid SolutionsFried, Stephen D.; Wang, Lee-Ping; Boxer, Steven G.; Ren, Pengyu; Pande, Vijay S.Journal of Physical Chemistry B (2013), 117 (50), 16236-16248CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)The elec. field created by a condensed-phase environment is a powerful and convenient descriptor for intermol. interactions. Not only does it provide a unifying language to compare many different types of interactions, but it also possesses clear connections to exptl. observables, such as vibrational Stark effects. We calc. here the elec. fields experienced by a vibrational chromophore (the carbonyl group of acetophenone) in an array of solvents of diverse polarities using mol. dynamics simulations with the AMOEBA polarizable force field. The mean and variance of the calcd. elec. fields correlate well with solvent-induced frequency shifts and band broadening, suggesting Stark effects as the underlying mechanism of these key soln.-phase spectral effects. Compared to fixed-charge and continuum models, AMOEBA was the only model examd. that could describe nonpolar, polar, and hydrogen bonding environments in a consistent fashion. Nevertheless, we found that fixed-charge force fields and continuum models were able to replicate some results of the polarizable simulations accurately, allowing us to clearly identify which properties and situations require explicit polarization and/or atomistic representations to be modeled properly, and to identify for which properties and situations simpler models are sufficient. We also discuss the ramifications of these results for modeling electrostatics in complex environments, such as proteins.
- 26Kuster, D. J.; Liu, C.; Fang, Z.; Ponder, J. W.; Marshall, G. R. High-Resolution Crystal Structures of Protein Helices Reconciled with Three-Centered Hydrogen Bonds and Multipole Electrostatics PLoS One 2015, 10 (4) e0123146 DOI: 10.1371/journal.pone.0123146Google ScholarThere is no corresponding record for this reference.
- 27El Hage, K.; Piquemal, J.-P.; Hobaika, Z.; Maroun, R. G.; Gresh, N. Substituent-Modulated Affinities of Halobenzene Derivatives to the HIV-1 Integrase Recognition Site. Analyses of the Interaction Energies by Parallel Quantum Chemical and Polarizable Molecular Mechanics J. Phys. Chem. A 2014, 118 (41) 9772– 9782 DOI: 10.1021/jp5079899Google ScholarThere is no corresponding record for this reference.
- 28MacDermaid, C. M.; Kaminski, G. A. Electrostatic Polarization Is Crucial for Reproducing pKa Shifts of Carboxylic Residues in Turkey Ovomucoid Third Domain J. Phys. Chem. B 2007, 111 (30) 9036– 9044 DOI: 10.1021/jp071284dGoogle Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmvFejtrg%253D&md5=9a6c4554ef7105b7a28d6e736df0325eElectrostatic Polarization Is Crucial for Reproducing pKa Shifts of Carboxylic Residues in Turkey Ovomucoid Third DomainMacDermaid, Christopher M.; Kaminski, George A.Journal of Physical Chemistry B (2007), 111 (30), 9036-9044CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)We have computed pKa shifts for carboxylic residues of the serine protease inhibitor turkey ovomucoid third domain (residues Asp7, Glu10, Glu19, Asp27, and Glu43). Both polarizable and nonpolarizable empirical force fields were employed. Hydration was represented by the surface generalized Born and Poisson-Boltzmann continuum model. The calcns. were carried out in the most phys. straightforward fashion, by directly comparing energies of the protonated and deprotonated protein forms, without any addnl. parameter fitting or adjustment. Our studies have demonstrated that (i) the Poisson-Boltzmann solvation model is more than adequate in reproducing pKa shifts, most likely due to its intrinsically many-body formalism; (ii) explicit treatment of electrostatic polarization included in our polarizable force field (PFF) calcns. appears to be crucial in reproducing the acidity const. shifts. The av. error of the PFF results was found to be as low as 0.58 pKa units, with the best fixed-charges av. deviation being 3.28 units. Therefore, the pKa shifts phenomena and the governing electrostatics are clearly many-body controlled in their intrinsic nature; (iii) our results confirm previously reported conclusions that pKa shifts for protein residues are controlled by the immediate environment of the residues in question, as opposed to long-range interactions in proteins. We are confident that our confirmation of the importance of explicit inclusion of polarization in empirical force fields for protein studies will be useful far beyond the immediate goal of accurate calcn. of acidity consts.
- 29Lemkul, J. A.; Savelyev, A.; MacKerell, A. D. Induced Polarization Influences the Fundamental Forces in DNA Base Flipping J. Phys. Chem. Lett. 2014, 5 (12) 2077– 2083 DOI: 10.1021/jz5009517Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXosl2qtr0%253D&md5=423e8ead8524a0af9ba630d967c4fe46Induced polarization influences the fundamental forces in DNA base flippingLemkul, Justin A.; Savelyev, Alexey; MacKerell, Alexander D.Journal of Physical Chemistry Letters (2014), 5 (12), 2077-2083CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)Base flipping in DNA is an important process involved in genomic repair and epigenetic control of gene expression. The driving forces for these processes are not fully understood, esp. in the context of the underlying dynamics of the DNA and solvent effects. Here, the authors studied double-stranded DNA oligomers that were previously characterized by imino proton exchange NMR using both additive and polarizable force fields. The results highlighted the importance of induced polarization on the base flipping process, yielding near-quant. agreement with exptl. measurements of the equil. between the base-paired and flipped states. Further, these simulations allow the authors to quantify for the 1st time the energetic implications of polarization on the flipping pathway. Free energy barriers to base flipping were reduced by changes in dipole moments of both the flipped bases that favored solvation of the bases in the open state and water mols. adjacent to the flipping base.
- 30Huang, J.; MacKerell, A. D. Induction of Peptide Bond Dipoles Drives Cooperative Helix Formation in the (AAQAA)3 Peptide Biophys. J. 2014, 107 (4) 991– 997 DOI: 10.1016/j.bpj.2014.06.038Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsValtbfI&md5=ac957b9b4ba06b568cbf922ff399d3e4Induction of Peptide Bond Dipoles Drives Cooperative Helix Formation in the (AAQAA)3 PeptideHuang, Jing; MacKerell, Alexander D. Jr.Biophysical Journal (2014), 107 (4), 991-997CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)Cooperativity is a central feature in the formation of secondary structures in proteins. However, the driving forces behind this cooperativity are poorly understood. The present work shows that the cooperativity of helix formation in the acetyl-(AAQAA)3-NH2 peptide is significantly enhanced using an empirical force field that explicitly includes the treatment of electronic polarizability. Polarizable simulations yield helical content consistent with exptl. measurements and indicate that the dependence of helical content on temp. is improved over additive models, though further sampling is required to fully validate this conclusion. Cooperativity is indicated by the peptide sampling either the coiled state or long helixes with relatively low populations of short helixes. The cooperativity is shown to be assocd. with enhanced dipole moments of the peptide backbone upon helix formation. These results indicate the polarizable force field to more accurately model peptide-folding cooperativity based on its phys. realistic treatment of electronic polarizability.
- 31Shi, Y.; Xia, Z.; Zhang, J.; Best, R.; Wu, C.; Ponder, J. W.; Ren, P. Polarizable Atomic Multipole-Based AMOEBA Force Field for Proteins J. Chem. Theory Comput. 2013, 9 (9) 4046– 4063 DOI: 10.1021/ct4003702Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFKrsrjN&md5=df5d457e466f177cc83c46ab7ff5c506Polarizable Atomic Multipole-Based AMOEBA Force Field for ProteinsShi, Yue; Xia, Zhen; Zhang, Jiajing; Best, Robert; Wu, Chuanjie; Ponder, Jay W.; Ren, PengyuJournal of Chemical Theory and Computation (2013), 9 (9), 4046-4063CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)Development of the AMOEBA (at. multipole optimized energetics for biomol. simulation) force field for proteins is presented. The current version (AMOEBA-2013) utilizes permanent electrostatic multipole moments through the quadrupole at each atom, and explicitly treats polarization effects in various chem. and phys. environments. The at. multipole electrostatic parameters for each amino acid residue type are derived from high-level gas phase quantum mech. calcns. via a consistent and extensible protocol. Mol. polarizability is modeled via a Thole-style damped interactive induction model based upon distributed at. polarizabilities. Inter- and intramol. polarization is treated in a consistent fashion via the Thole model. The intramol. polarization model ensures transferability of electrostatic parameters among different conformations, as demonstrated by the agreement between QM and AMOEBA electrostatic potentials, and dipole moments of dipeptides. The backbone and side chain torsional parameters were detd. by comparing to gas-phase QM (RI-TRIM MP2/CBS) conformational energies of dipeptides and to statistical distributions from the Protein Data Bank. Mol. dynamics simulations are reported for short peptides in explicit water to examine their conformational properties in soln. Overall the calcd. conformational free energies and J-coupling consts. are consistent with PDB statistics and exptl. NMR results, resp. In addn., the exptl. crystal structures of a no. of proteins are well maintained during mol. dynamics (MD) simulation. While further calcns. are necessary to fully validate the force field, initial results suggest the AMOEBA polarizable multipole force field is able to describe the structure and energetics of peptides and proteins, in both gas-phase and soln. environments.
- 32Laury, M. L.; Wang, L.-P.; Pande, V. S.; Head-Gordon, T. L.; Ponder, J. W. Revised Parameters for the AMOEBA Polarizable Atomic Multipole Water Model J. Phys. Chem. B 2015, 119 (29) 9423– 9437 DOI: 10.1021/jp510896nGoogle Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXislSmsL8%253D&md5=254aba3db5c0fbf6f70f4b8036048acbRevised Parameters for the AMOEBA Polarizable Atomic Multipole Water ModelLaury, Marie L.; Wang, Lee-Ping; Pande, Vijay S.; Head-Gordon, Teresa; Ponder, Jay W.Journal of Physical Chemistry B (2015), 119 (29), 9423-9437CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)A set of improved parameters for the AMOEBA polarizable at. multipole water model is developed. An automated procedure, ForceBalance, is used to adjust model parameters to enforce agreement with ab initio-derived results for water clusters and exptl. data for a variety of liq. phase properties across a broad temp. range. The values reported here for the new AMOEBA14 water model represent a substantial improvement over the previous AMOEBA03 model. The AMOEBA14 model accurately predicts the temp. of max. d. and qual. matches the exptl. d. curve across temps. from 249 to 373 K. Excellent agreement is obsd. for the AMOEBA14 model in comparison to exptl. properties as a function of temp., including the second virial coeff., enthalpy of vaporization, isothermal compressibility, thermal expansion coeff., and dielec. const. The viscosity, self-diffusion const., and surface tension are also well reproduced. In comparison to high-level ab initio results for clusters of 2-20 water mols., the AMOEBA14 model yields results similar to AMOEBA03 and the direct polarization iAMOEBA models. With advances in computing power, calibration data, and optimization techniques, we recommend the use of the AMOEBA14 water model for future studies employing a polarizable water model.
- 33Wang, Q.; Rackers, J. A.; He, C.; Qi, R.; Narth, C.; Lagardère, L.; Gresh, N.; Ponder, J. W.; Piquemal, J.-P.; Ren, P. A General Model for Treating Short-Range Electrostatic Penetration in a Molecular Mechanics Force Field J. Chem. Theory Comput. 2015, 11 (6) 2609– 2618 DOI: 10.1021/acs.jctc.5b00267Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXntlCntrw%253D&md5=0ccb1ad26499eccc00a0a7ea0653af67General Model for Treating Short-Range Electrostatic Penetration in a Molecular Mechanics Force FieldWang, Qiantao; Rackers, Joshua A.; He, Chenfeng; Qi, Rui; Narth, Christophe; Lagardere, Louis; Gresh, Nohad; Ponder, Jay W.; Piquemal, Jean-Philip; Ren, PengyuJournal of Chemical Theory and Computation (2015), 11 (6), 2609-2618CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)Classical mol. mechanics force fields typically model interat. electrostatic interactions with point charges or multipole expansions, which can fail for atoms in close contact due to the lack of a description of penetration effects between their electron clouds. These short-range penetration effects can be significant and are essential for accurate modeling of intermol. interactions. In this work we report parametrization of an empirical charge-charge function previously reported to correct for the missing penetration term in std. mol. mechanics force fields. For this purpose, we have developed a database (S101×7) of 101 unique mol. dimers, each at 7 different intermol. distances. Electrostatic, induction/polarization, repulsion, and dispersion energies, as well as the total interaction energy for each complex in the database are calcd. using the SAPT2 + method. This empirical penetration model significantly improves agreement between point multipole and quantum mech. electrostatic energies across the set of dimers and distances, while using only a limited set of parameters for each chem. element. Given the simplicity and effectiveness of the model, we expect the electrostatic penetration correction will become a std. component of future mol. mechanics force fields.
- 34Lagardère, L.; Lipparini, F.; Polack, E.; Stamm, B.; Schnieders, M.; Cances, E.; Ren, P.; Maday, Y.; Piquemal, J.-P. Scalable Evaluation of Polarization Energy and Associated Forces in Polarizable Molecular Dynamics: II.Towards Massively Parallel Computations Using Smooth Particle Mesh Ewald J. Chem. Theory Comput. 2015, 11 (6) 2589– 2599 DOI: 10.1021/acs.jctc.5b00171Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXnvFClsbo%253D&md5=c0657f8139af4f0e84812b3bb7490059Scalable Evaluation of Polarization Energy and Associated Forces in Polarizable Molecular Dynamics: II. Toward Massively Parallel Computations Using Smooth Particle Mesh EwaldLagardere, Louis; Lipparini, Filippo; Polack, Etienne; Stamm, Benjamin; Cances, Eric; Schnieders, Michael; Ren, Pengyu; Maday, Yvon; Piquemal, Jean-PhilipJournal of Chemical Theory and Computation (2015), 11 (6), 2589-2599CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)The authors present a parallel implementation of point dipole-based polarizable force fields for mol. dynamics (MD) simulations with periodic boundary conditions (PBC). The smooth particle mesh Ewald technique is combined with two optimal iterative strategies, namely, a preconditioned conjugate gradient solver and a Jacobi solver in conjunction with the direct inversion in the iterative subspace for convergence acceleration, to solve the polarization equations. Both solvers exhibit very good parallel performances and overall very competitive timings in an energy and force computation needed to perform a MD step. Various tests on large systems are provided in the context of the polarizable AMOEBA force field as implemented in the newly developed Tinker-HP package, which is the 1st implementation of a polarizable model that makes large-scale expts. for massively parallel PBC point dipole models possible. Using a large no. of cores offers a significant acceleration of the overall process involving the iterative methods within the context of SPME and a noticeable improvement of the memory management, giving access to very large systems (hundreds of thousands of atoms) as the algorithm naturally distributes the data on different cores. Coupled with advanced MD techniques, gains ranging from 2 to 3 orders of magnitude in time are now possible compared to nonoptimized, sequential implementations, giving new directions for polarizable mol. dynamics with periodic boundary conditions using massively parallel implementations.
- 35Albaugh, A.; Demerdash, O.; Head-Gordon, T. An Efficient and Stable Hybrid Extended Lagrangian/self-Consistent Field Scheme for Solving Classical Mutual Induction J. Chem. Phys. 2015, 143 (17) 174104 DOI: 10.1063/1.4933375Google ScholarThere is no corresponding record for this reference.
- 36Lindert, S.; Bucher, D.; Eastman, P.; Pande, V.; McCammon, J. A. Accelerated Molecular Dynamics Simulations with the AMOEBA Polarizable Force Field on Graphics Processing Units J. Chem. Theory Comput. 2013, 9 (11) 4684– 4691 DOI: 10.1021/ct400514pGoogle Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1WltbvK&md5=db44fd3f64a298b6870a50a850aef72aAccelerated Molecular Dynamics Simulations with the AMOEBA Polarizable Force Field on Graphics Processing UnitsLindert, Steffen; Bucher, Denis; Eastman, Peter; Pande, Vijay; McCammon, J. AndrewJournal of Chemical Theory and Computation (2013), 9 (11), 4684-4691CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)The accelerated mol. dynamics (aMD) method has recently been shown to enhance the sampling of biomols. in mol. dynamics (MD) simulations, often by several orders of magnitude. Here, the authors describe an implementation of the aMD method for the OpenMM application layer that takes full advantage of graphics processing units (GPUs) computing. The aMD method is shown to work in combination with the AMOEBA polarizable force field (AMOEBA-aMD), allowing the simulation of long time-scale events with a polarizable force field. Benchmarks are provided to show that the AMOEBA-aMD method is efficiently implemented and produces accurate results in its std. parametrization. For the BPTI protein, the protein structure described with AMOEBA remains stable even on the extended time scales accessed at high levels of accelerations. For the DNA repair metalloenzyme endonuclease IV, the use of the AMOEBA force field is a significant improvement over fixed charged models for describing the enzyme active-site. The new AMOEBA-aMD method is publicly available (http://wiki.simtk.org/openmm/VirtualRepository) and promises to be interesting for studying complex systems that can benefit from both the use of a polarizable force field and enhanced sampling.
- 37Peng, X.; Zhang, Y.; Chu, H.; Li, G. Free Energy Simulations with the AMOEBA Polarizable Force Field and Metadynamics on GPU Platform J. Comput. Chem. 2016, 37 (6) 614– 622 DOI: 10.1002/jcc.24227Google ScholarThere is no corresponding record for this reference.
- 38Wu, J. C.; Chattree, G.; Ren, P. Automation of AMOEBA Polarizable Force Field Parameterization for Small Molecules Theor. Chem. Acc. 2012, 131 (3) 1138 DOI: 10.1007/s00214-012-1138-6Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2srms1OntA%253D%253D&md5=5432a389f20925526b9b0c25c9646ef0Automation of AMOEBA polarizable force field parameterization for small moleculesWu Johnny C; Chattree Gaurav; Ren PengyuTheoretical chemistry accounts (2012), 131 (3), 1138 ISSN:1432-881X.A protocol to generate parameters for the AMOEBA polarizable force field for small organic molecules has been established, and polarizable atomic typing utility, Poltype, which fully automates this process, has been implemented. For validation, we have compared with quantum mechanical calculations of molecular dipole moments, optimized geometry, electrostatic potential, and conformational energy for a variety of neutral and charged organic molecules, as well as dimer interaction energies of a set of amino acid side chain model compounds. Furthermore, parameters obtained in gas phase are substantiated in liquid-phase simulations. The hydration free energy (HFE) of neutral and charged molecules have been calculated and compared with experimental values. The RMS error for the HFE of neutral molecules is less than 1 kcal/mol. Meanwhile, the relative error in the predicted HFE of salts (cations and anions) is less than 3% with a correlation coefficient of 0.95. Overall, the performance of Poltype is satisfactory and provides a convenient utility for applications such as drug discovery. Further improvement can be achieved by the systematic study of various organic compounds, particularly ionic molecules, and refinement and expansion of the parameter database.
- 39Manzoni, F.; Söderhjelm, P. Prediction of Hydration Free Energies for the SAMPL4 Data Set with the AMOEBA Polarizable Force Field J. Comput.-Aided Mol. Des. 2014, 28 (3) 235– 244 DOI: 10.1007/s10822-014-9733-3Google ScholarThere is no corresponding record for this reference.
- 40Muddana, H. S.; Fenley, A. T.; Mobley, D. L.; Gilson, M. K. The SAMPL4 Host–guest Blind Prediction Challenge: An Overview J. Comput.-Aided Mol. Des. 2014, 28 (4) 305– 317 DOI: 10.1007/s10822-014-9735-1Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjs1Ggs74%253D&md5=04ade7377b0bee4428baba44db3d2a83The SAMPL4 host-guest blind prediction challenge: an overviewMuddana, Hari S.; Fenley, Andrew T.; Mobley, David L.; Gilson, Michael K.Journal of Computer-Aided Molecular Design (2014), 28 (4), 305-317CODEN: JCADEQ; ISSN:0920-654X. (Springer)A review. Prospective validation of methods for computing binding affinities can help assess their predictive power and thus set reasonable expectations for their performance in drug design applications. Supramol. host-guest systems are excellent model systems for testing such affinity prediction methods, because their small size and limited conformational flexibility, relative to proteins, allows higher throughput and better numerical convergence. The SAMPL4 prediction challenge therefore included a series of host-guest systems, based on two hosts, cucurbit[7]uril and octa-acid. Binding affinities in aq. soln. were measured exptl. for a total of 23 guest mols. Participants submitted 35 sets of computational predictions for these host-guest systems, based on methods ranging from simple docking, to extensive free energy simulations, to quantum mech. calcns. Over half of the predictions provided better correlations with expt. than two simple null models, but most methods underperformed the null models in terms of root mean squared error and linear regression slope. Interestingly, the overall performance across all SAMPL4 submissions was similar to that for the prior SAMPL3 host-guest challenge, although the experimentalists took steps to simplify the current challenge. While some methods performed fairly consistently across both hosts, no single approach emerged as consistent top performer, and the nonsystematic nature of the various submissions made it impossible to draw definitive conclusions regarding the best choices of energy models or sampling algorithms. Salt effects emerged as an issue in the calcn. of abs. binding affinities of cucurbit[7]uril-guest systems, but were not expected to affect the relative affinities significantly. Useful directions for future rounds of the challenge might involve encouraging participants to carry out some calcns. that replicate each others' studies, and to systematically explore parameter options.
- 41Ren, P. Y.; Ponder, J. W. Consistent Treatment of Inter- and Intramolecular Polarization in Molecular Mechanics Calculations J. Comput. Chem. 2002, 23 (16) 1497– 1506 DOI: 10.1002/jcc.10127Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XosF2rtr4%253D&md5=4f43548e95124d23ba655451cd332232Consistent treatment of inter- and intramolecular polarization in molecular mechanics calculationsRen, Pengyu; Ponder, Jay W.Journal of Computational Chemistry (2002), 23 (16), 1497-1506CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)A protocol is described for the treatment of mol. polarization in force field calcns. The resulting model is consistent in that both inter- and intramol. polarization are handled within a single scheme. An anal. formula for removing intramol. polarization from a set of at. multipoles for an arbitrary static structure or conformation is given. With the help of the intramol. polarization, these permanent at. multipoles can then be applied in modeling alternative conformations of a mol. Equipped with this simple technique, one can derive transferable electrostatic parameters for peptides and proteins using flexible model compds. such as dipeptides. The proposed procedure is tested for its ability to describe the electrostatic potential around various configurations of the N-methylacetamide dimer. The effect of different intramol. polarization schemes on the accuracy of a force field model of the electrostatic potential of alanine dipeptide is investigated. A group-based scheme for including direct intramol. polarization is shown to be most successful in accounting for the conformational dependence of electrostatic potentials.
- 42Ren, P. Y.; Ponder, J. W. Polarizable Atomic Multipole Water Model for Molecular Mechanics Simulation J. Phys. Chem. B 2003, 107 (24) 5933– 5947 DOI: 10.1021/jp027815+Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjvFOhsro%253D&md5=f9cc56cc91cc9c86df686004dd9f8ff5Polarizable Atomic Multipole Water Model for Molecular Mechanics SimulationRen, Pengyu; Ponder, Jay W.Journal of Physical Chemistry B (2003), 107 (24), 5933-5947CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)A new classical empirical potential is proposed for water. The model uses a polarizable at. multipole description of electrostatic interactions. Multipoles through the quadrupole are assigned to each at. center based on a distributed multipole anal. (DMA) derived from large basis set MO calcns. on the water monomer. Polarization is treated via self-consistent induced at. dipoles. A modified version of Thole's interaction model is used to damp induction at short range. Repulsion-dispersion (vdW) effects are computed from a buffered 14-7 potential. In a departure from most current water potentials, we find that significant vdW parameters are necessary on hydrogen as well as oxygen. The new potential is fully flexible and has been tested vs. a variety of exptl. data and quantum calcns. for small clusters, liq. water, and ice. Overall, excellent agreement with exptl. and high level ab initio results is obtained for numerous properties, including cluster structures and energetics and bulk thermodn. and structural measures. The parametrization scheme described here is easily extended to other mol. systems, and the resulting water potential should provide a useful explicit solvent model for org. solutes and biopolymer modeling.
- 43Thole, B. T. Molecular Polarizabilities Calculated with a Modified Dipole Interaction Chem. Phys. 1981, 59 (3) 341– 350 DOI: 10.1016/0301-0104(81)85176-2Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3MXltl2jurk%253D&md5=a92d26bef31ef7e26a244c3f15d5b8a6Molecular polarizabilities calculated with a modified dipole interactionThole, B. T.Chemical Physics (1981), 59 (3), 341-50CODEN: CMPHC2; ISSN:0301-0104.The point dipole interaction model for mol. polarizability recently proposed by J. Applequist, et al., (1972) is modified by replacing the point dipole interaction by an interaction between smeared out dipoles. Rules are developed to indicate plausible forms for this modified interaction. The polarizabilities of a wide range of chem. different mols. can be calcd., using for each atom one polarizability independent of its chem. environment. The errors are comparable to exptl. uncertainty. Special care is taken to produce a model that tends to avoid infinite polarizabilities without use of cutoffs at short distances.
- 44Jakalian, A.; Jack, D. B.; Bayly, C. I. Fast, Efficient Generation of High-Quality Atomic Charges. AM1-BCC Model: II. Parameterization and Validation J. Comput. Chem. 2002, 23 (16) 1623– 1641 DOI: 10.1002/jcc.10128Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XosF2rt74%253D&md5=3f2b738617bb17b2898f7ac4d751d7ecFast, efficient generation of high-quality atomic charges. AM1-BCC model: II. parameterization and validationJakalian, Araz; Jack, David B.; Bayly, Christopher I.Journal of Computational Chemistry (2002), 23 (16), 1623-1641CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)We present the first global parameterization and validation of a novel charge model, called AM1-BCC, which quickly and efficiently generates high-quality at. charges for computer simulations of org. mols. in polar media. The goal of the charge model is to produce at. charges that emulate the HF/6-31G* electrostatic potential (ESP) of a mol. Underlying electronic structure features, including formal charge and electron delocalization, are first captured by AM1 population charges; simple additive bond charge corrections (BCCs) are then applied to these AM1 at. charges to produce the AM1-BCC charges. The parameterization of BCCs was carried out by fitting to the HF/6-31G* ESP of a training set of >2700 mols. Most org. functional groups and their combinations were sampled, as well as an extensive variety of cyclic and fused bicyclic heteroaryl systems. The resulting BCC parameters allow the AM1-BCC charging scheme to handle virtually all types of org. compds. listed in The Merck Index and the NCI Database. Validation of the model was done through comparisons of hydrogen-bonded dimer energies and relative free energies of solvation using AM1-BCC charges in conjunction with the 1994 Cornell et al. forcefield for AMBER. Homo-dimer and hetero-dimer hydrogen-bond energies of a diverse set of org. mols. were reproduced to within 0.95 kcal/mol RMS deviation from the ab initio values, and for DNA dimers the energies were within 0.9 kcal/mol RMS deviation from ab initio values. The calcd. relative free energies of solvation for a diverse set of monofunctional isosteres were reproduced to within 0.69 kcal/mol of expt. In all these validation tests, AMBER with the AM1-BCC charge model maintained a correlation coeff. above 0.96. Thus, the parameters presented here for use with the AM1-BCC method present a fast, accurate, and robust alternative to HF/6-31G* ESP-fit charges for general use with the AMBER force field in computer simulations involving org. small mols.
- 45Bayly, C. I.; Cieplak, P.; Cornell, W. D.; Kollman, P. A. A Well-Behaved Electrostatic Potential Based Method Using Charge Restraints for Deriving Atomic Charges: The RESP Model J. Phys. Chem. 1993, 97, 10269– 10280 DOI: 10.1021/j100142a004Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXlvVyqsLs%253D&md5=e65c6a556ffc174df4f327687912a0bdA well-behaved electrostatic potential based method using charge restraints for deriving atomic charges: the RESP modelBayly, Christopher I.; Cieplak, Piotr; Cornell, Wendy; Kollman, Peter A.Journal of Physical Chemistry (1993), 97 (40), 10269-80CODEN: JPCHAX; ISSN:0022-3654.The authors present a new approach to generating electrostatic potential (ESP) derived charges for mols. The major strength of electrostatic potential derived charges is that they optimally reproduce the intermol. interaction properties of mols. with a simple two-body additive potential, provided, of course, that a suitably accurate level of quantum mech. calcn. is used to derive the ESP around the mol. Previously, the major weaknesses of these charges have been that they were not easily transferably between common functional groups in related mols., they have often been conformationally dependent, and the large charges that frequently occur can be problematic for simulating intramol. interactions. Introducing restraints in the form of a penalty function into the fitting process considerably reduces the above problems, with only a minor decrease in the quality of the fit to the quantum mech. ESP. Several other refinements in addn. to the restrained electrostatic potential (RESP) fit yield a general and algorithmic charge fitting procedure for generating atom-centered point charges. This approach can thus be recommended for general use in mol. mechanics, mol. dynamics, and free energy calcns. for any org. or bioorg. system.
- 46Wang, J.; Wolf, R. M.; Caldwell, J. W.; Kollman, P. A.; Case, D. A. Development and Testing of a General Amber Force Field J. Comput. Chem. 2004, 25 (9) 1157– 1174 DOI: 10.1002/jcc.20035Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXksFakurc%253D&md5=2992017a8cf51f89290ae2562403b115Development and testing of a general Amber force fieldWang, Junmei; Wolf, Romain M.; Caldwell, James W.; Kollman, Peter A.; Case, David A.Journal of Computational Chemistry (2004), 25 (9), 1157-1174CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)We describe here a general Amber force field (GAFF) for org. mols. GAFF is designed to be compatible with existing Amber force fields for proteins and nucleic acids, and has parameters for most org. and pharmaceutical mols. that are composed of H, C, N, O, S, P, and halogens. It uses a simple functional form and a limited no. of atom types, but incorporates both empirical and heuristic models to est. force consts. and partial at. charges. The performance of GAFF in test cases is encouraging. In test I, 74 crystallog. structures were compared to GAFF minimized structures, with a root-mean-square displacement of 0.26 Å, which is comparable to that of the Tripos 5.2 force field (0.25 Å) and better than those of MMFF 94 and CHARMm (0.47 and 0.44 Å, resp.). In test II, gas phase minimizations were performed on 22 nucleic acid base pairs, and the minimized structures and intermol. energies were compared to MP2/6-31G* results. The RMS of displacements and relative energies were 0.25 Å and 1.2 kcal/mol, resp. These data are comparable to results from Parm99/RESP (0.16 Å and 1.18 kcal/mol, resp.), which were parameterized to these base pairs. Test III looked at the relative energies of 71 conformational pairs that were used in development of the Parm99 force field. The RMS error in relative energies (compared to expt.) is about 0.5 kcal/mol. GAFF can be applied to wide range of mols. in an automatic fashion, making it suitable for rational drug design and database searching.
- 47Wang, J.; Wang, W.; Kollman, P. A.; Case, D. A. Automatic Atom Type and Bond Type Perception in Molecular Mechanical Calculations J. Mol. Graphics Modell. 2006, 25 (2) 247– 260 DOI: 10.1016/j.jmgm.2005.12.005Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xps1Gis7g%253D&md5=8031a21d2784d5dea12e70868522aa61Automatic atom type and bond type perception in molecular mechanical calculationsWang, Junmei; Wang, Wei; Kollman, Peter A.; Case, David A.Journal of Molecular Graphics & Modelling (2006), 25 (2), 247-260CODEN: JMGMFI; ISSN:1093-3263. (Elsevier Inc.)In mol. mechanics (MM) studies, atom types and/or bond types of mols. are needed to det. prior to energy calcns. The authors present here an automatic algorithm of perceiving atom types that are defined in a description table, and an automatic algorithm of assigning bond types just based on at. connectivity. The algorithms have been implemented in a new module of the AMBER packages. This auxiliary module, antechamber (roughly meaning "before AMBER"), can be applied to generate necessary inputs of leap-the AMBER program to generate topologies for minimization, mol. dynamics, etc., for most org. mols. The algorithms behind the manipulations may be useful for other mol. mech. packages as well as applications that need to designate atom types and bond types.
- 48Stone, A. J. Distributed Multipole Analysis, or How to Describe a Molecular Charge Distribution Chem. Phys. Lett. 1981, 83 (2) 233– 239 DOI: 10.1016/0009-2614(81)85452-8Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3MXmt1yitbY%253D&md5=1a7ac695fa444006688ea669d36a3d55Distributed multipole analysis, or how to describe a molecular charge distributionStone, A. J.Chemical Physics Letters (1981), 83 (2), 233-9CODEN: CHPLBC; ISSN:0009-2614.A method of analyzing mol. wavefunctions is described. It can be regarded as an extension of Mulliken population anal., and can be used both to give a qual. or quant. picture of the mol. charge distribution, and in the accurate evaluation of mol. multipole moments of arbitrary order with negligible computational effort.
- 49Stone, A. J.; Alderton, M. Distributed Multipole Analysis: Methods and Applications Mol. Phys. 1985, 56 (5) 1047– 1064 DOI: 10.1080/00268978500102891Google ScholarThere is no corresponding record for this reference.
- 50Shi, Y.; Wu, C. J.; Ponder, J. W.; Ren, P. Y. Multipole Electrostatics in Hydration Free Energy Calculations J. Comput. Chem. 2011, 32 (5) 967– 977 DOI: 10.1002/jcc.21681Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXitleju7s%253D&md5=364014fda294cf4cfcb72253a38df389Multipole electrostatics in hydration free energy calculationsShi, Yue; Wu, Chuan-Jie; Ponder, Jay W.; Ren, Peng-YuJournal of Computational Chemistry (2011), 32 (5), 967-977CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)Hydration free energy (HFE) is generally used for evaluating mol. soly., which is an important property for pharmaceutical and chem. engineering processes. Accurately predicting HFE is also recognized as one fundamental capability of mol. mechanics force field. Here, the authors present a systematic investigation on HFE calcns. with AMOEBA polarizable force field at various parameterization and simulation conditions. The HFEs of seven small org. mols. have been obtained alchem. using the Bennett Acceptance Ratio method. The authors have compared two approaches to derive the at. multipoles from quantum mech. calcns.: one directly from the new distributed multipole anal. and the other involving fitting to the electrostatic potential around the mols. Wave functions solved at the MP2 level with four basis sets (6-311G*, 6-311++G(2d,2p), cc-pVTZ, and aug-cc-pVTZ) are used to derive the at. multipoles. HFEs from all four basis sets show a reasonable agreement with exptl. data (root mean square error 0.63 kcal/mol for aug-cc-pVTZ). The aug-cc-pVTZ gives the best performance when used with AMOEBA, and 6-311++G(2d,2p) is comparable but more efficient for larger systems. The results suggest that the inclusion of diffuse basis functions is important for capturing intermol. interactions. The effect of long-range correction to van der Waals interaction on the hydration free energies is about 0.1 kcal/mol when the cutoff is 12Å, and increases linearly with the no. of atoms in the solute/ligand. In addn., the authors also discuss the results from a hybrid approach that combines polarizable solute with fixed-charge water in the HFE calcn.
- 51Ren, P. Y.; Ponder, J. W. Temperature and Pressure Dependence of the AMOEBA Water Model J. Phys. Chem. B 2004, 108 (35) 13427– 13437 DOI: 10.1021/jp0484332Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmt12ktbs%253D&md5=e8c36c8fb511134c7e861b6b11cd999aTemperature and Pressure Dependence of the AMOEBA Water ModelRen, Pengyu; Ponder, Jay W.Journal of Physical Chemistry B (2004), 108 (35), 13427-13437CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)The temp. and pressure dependence of the previously developed polarizable at.-multipole-based AMOEBA water potential is explored. The energetic, structural, and dynamical properties of liq. water are investigated via mol. dynamics simulations at various temps. ranging from 248 K to 360 K and pressures up to 5000 atm. The AMOEBA model, derived solely from known gas-phase and room-temp. liq. properties, produces a max. liq. d. around 290 K at 1 atm. The quant. agreement between AMOEBA and expt. is good in general for d., heat of vaporization, radial distribution functions, magnetic shielding, self-diffusion, and static dielec. const. Based on comparison of two variants of AMOEBA water, as well as results from other water potentials, it is suggested that the temp. at which the max. d. occurs is closely related to the tetrahedral hydrogen-bonding network in the bulk. Explicit dipole polarization and internal geometry in the liq. play vital roles in detg. the self-diffusion and dielec. consts. The development of the AMOEBA model demonstrates that a realistic and well-balanced at. potential requires a sophisticated electrostatic description and inclusion of many-body polarization. Within the current polarizable at. multipole framework, a potential derived from limited gas phase and condensed phase properties can be applied across a range of phys. and thermodn. environments.
- 52Ponder, J. TINKER: Software Tools for Molecular Design; Washington University School of Medicine: St. Louis, MO, 2001.Google ScholarThere is no corresponding record for this reference.
- 53Case, D. A.; Babin, V.; Berryman, J. T.; Betz, R. M.; Cai, Q.; Cerutti, D. S.; Cheatham, T. E. I.; Darden, T. A.; Duke, R. E.; Gohlke, H.; Goetz, A. W.; Gusarov, S.; Homeyer, N.; Janowski, P. A.; Kaus, J.; Kolossváry, I.; Kovalenko, A.; Lee, T. S.; LeGrand, S.; Luchko, T.; Luo, R.; Madej, B.; Merz, K. M., Jr.; Paesani, F.; Roe, D. R.; Roitberg, A. E.; Sagui, C.; Salomon-Ferrer, R.; Seabra, G.; Simmerling, C. L.; Smith, W.; Swails, J. M.; Walker, R. C.; Wang, J.; Wolf, R. M.; Wu, X.; Kollman, P. A. AMBER 14; University of California: San Francisco, CA, 2014.Google ScholarThere is no corresponding record for this reference.
- 54Pastor, R. W.; Brooks, B. R.; Szabo, A. An Analysis of the Accuracy of Langevin and Molecular Dynamics Algorithms Mol. Phys. 1988, 65, 1409– 1419 DOI: 10.1080/00268978800101881Google ScholarThere is no corresponding record for this reference.
- 55Loncharich, R. J.; Brooks, B. R.; Pastor, R. W. Langevin Dynamics of Peptides: The Frictional Dependence of Isomerization Rates of N-Acetylalanyl-N′-methylamide Biopolymers 1992, 32 (5) 523– 535 DOI: 10.1002/bip.360320508Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XisFGqu7o%253D&md5=9209a0b3485915887d1b03fefcbadc35Langevin dynamics of peptides: the frictional dependence of isomerization rates of N-acetylalanyl-N'-methylamideLoncharich, Richard J.; Brooks, Bernard R.; Pastor, Richard W.Biopolymers (1992), 32 (5), 523-35CODEN: BIPMAA; ISSN:0006-3525.The rate const. for the transition between the equatorial and axial conformations of N-acetylalanyl-N'-methylamide has been detd. from Langevin dynamics (LD) simulations with no explicit solvent. The isomerization rate is max. at collision frequency γ = 2 ps-1, shows diffusive character for γ ≥ 10 ps-1, but does not approach zero even at γ = 0.01 ps-1. This behavior differs from that found for a one-dimensional bistable potential and indicates that both collisional energy transfer with solvent and vibrational energy transfer between internal modes are important in the dynamics of barrier crossing for this system. It is suggested that conformational searches of peptides be carried out using LD with a collision frequency that maximizes the isomerization rate (i.e., γ ≈ 2 ps-1). This method is expected to be more efficient than either mol. dynamics in vacuo (which corresponds to LD with γ = 0) or mol. dynamics in solvent (where dynamics is largely diffusive).
- 56Izaguirre, J. A.; Catarello, D. P.; Wozniak, J. M.; Skeel, R. D. Langevin Stabilization of Molecular Dynamics J. Chem. Phys. 2001, 114, 2090– 2098 DOI: 10.1063/1.1332996Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXms1eltQ%253D%253D&md5=6f5c141b113cc7a8cacea7e15f9fb007Langevin stabilization of molecular dynamicsIzaguirre, Jesus A.; Catarello, Daniel P.; Wozniak, Justin M.; Skeel, Robert D.Journal of Chemical Physics (2001), 114 (5), 2090-2098CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)In this paper we show the possibility of using very mild stochastic damping to stabilize long time step integrators for Newtonian mol. dynamics. More specifically, stable and accurate integrations are obtained for damping coeffs. that are only a few percent of the natural decay rate of processes of interest, such as the velocity autocorrelation function. Two new multiple time stepping integrators, Langevin Molly (LM) and Brunger-Brooks-Karplus-Molly (BBK-M), are introduced in this paper. Both use the mollified impulse method for the Newtonian term. LM uses a discretization of the Langevin equation that is exact for the const. force, and BBK-M uses the popular Brunger-Brooks-Karplus integrator (BBK). These integrators, along with an extrapolative method called LN, are evaluated across a wide range of damping coeff. values. When large damping coeffs. are used, as one would for the implicit modeling of solvent mols., the method LN is superior, with LM closely following. However, with mild damping of 0.2 ps-1, LM produces the best results, allowing long time steps of 14 fs in simulations contg. explicitly modeled flexible water. With BBK-M and the same damping coeff., time steps of 12 fs are possible for the same system. Similar results are obtained for a solvated protein-DNA simulation of estrogen receptor ER with estrogen response element ERE. A parallel version of BBK-M runs nearly three times faster than the Verlet-I/r-RESPA (reversible ref. system propagator algorithm) when using the largest stable time step on each one, and it also parallelizes well. The computation of diffusion coeffs. for flexible water and ER/ERE shows that when mild damping of up to 0.2 ps-1 is used the dynamics are not significantly distorted.
- 57Berendsen, H. J. C.; Postma, J. P. M.; van Gunsteren, W. F.; DiNola, A.; Haak, J. R. Molecular Dynamics with Coupling to an External Bath J. Chem. Phys. 1984, 81 (8) 3684 DOI: 10.1063/1.448118Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2cXmtlGksbY%253D&md5=5510dc00297d63b91ee3a7a4ae5aacb1Molecular dynamics with coupling to an external bathBerendsen, H. J. C.; Postma, J. P. M.; Van Gunsteren, W. F.; DiNola, A.; Haak, J. R.Journal of Chemical Physics (1984), 81 (8), 3684-90CODEN: JCPSA6; ISSN:0021-9606.In mol. dynamics (MD) simulations, the need often arises to maintain such parameters as temp. or pressure rather than energy and vol., or to impose gradients for studying transport properties in nonequil. MD. A method is described to realize coupling to an external bath with const. temp. or pressure with adjustable time consts. for the coupling. The method is easily extendable to other variables and to gradients, and can be applied also to polyat. mols. involving internal constraints. The influence of coupling time consts. on dynamical variables is evaluated. A leap-frog algorithm is presented for the general case involving constraints with coupling to both a const. temp. and a const. pressure bath.
- 58Sagui, C.; Pedersen, L. G.; Darden, T. A. Towards an Accurate Representation of Electrostatics in Classical Force Fields: Efficient Implementation of Multipolar Interactions in Biomolecular Simulations J. Chem. Phys. 2004, 120 (1) 73– 87 DOI: 10.1063/1.1630791Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXotVw%253D&md5=b9cf8b78c1d35fd103a5b2147c27b471Towards an accurate representation of electrostatics in classical force fields: Efficient implementation of multipolar interactions in biomolecular simulationsSagui, Celeste; Pedersen, Lee G.; Darden, Thomas A.Journal of Chemical Physics (2004), 120 (1), 73-87CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)The accurate simulation of biol. active macromols. faces serious limitations that originate in the treatment of electrostatics in the empirical force fields. The current use of "partial charges" is a significant source of errors, since these vary widely with different conformations. By contrast, the mol. electrostatic potential (MEP) obtained through the use of a distributed multipole moment description, has been shown to converge to the quantum MEP outside the van der Waals surface, when higher order multipoles are used. However, in spite of the considerable improvement to the representation of the electronic cloud, higher order multipoles are not part of current classical biomol. force fields due to the excessive computational cost. In this paper we present an efficient formalism for the treatment of higher order multipoles in Cartesian tensor formalism. The Ewald "direct sum" is evaluated through a McMurchie-Davidson formalism [L. McMurchie and E. Davidson, J. Comput. Phys. 26, 218 (1978)]. The "reciprocal sum" has been implemented in three different ways: using an Ewald scheme, a particle mesh Ewald (PME) method, and a multigrid-based approach. We find that even though the use of the McMurchie-Davidson formalism considerably reduces the cost of the calcn. with respect to the std. matrix implementation of multipole interactions, the calcn. in direct space remains expensive. When most of the calcn. is moved to reciprocal space via the PME method, the cost of a calcn. where all multipolar interactions (up to hexadecapole-hexadecapole) are included is only about 8.5 times more expensive than a regular AMBER 7 [D. A. Pearlman et al., Comput. Phys. Commun. 91, 1 (1995)] implementation with only charge-charge interactions. The multigrid implementation is slower but shows very promising results for parallelization. It provides a natural way to interface with continuous, Gaussian-based electrostatics in the future. It is hoped that this new formalism will facilitate the systematic implementation of higher order multipoles in classical biomol. force fields.
- 59Cerutti, D. S.; Duke, R.; Freddolino, P. L.; Fan, H.; Lybrand, T. P. A Vulnerability in Popular Molecular Dynamics Packages Concerning Langevin and Andersen Dynamics J. Chem. Theory Comput. 2008, 4 (10) 1669– 1680 DOI: 10.1021/ct8002173Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtV2lurfO&md5=d6cb4ac701c7c0268114a54030cad05fA Vulnerability in Popular Molecular Dynamics Packages Concerning Langevin and Andersen DynamicsCerutti, David S.; Duke, Robert; Freddolino, Peter L.; Fan, Hao; Lybrand, Terry P.Journal of Chemical Theory and Computation (2008), 4 (10), 1669-1680CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)We report a serious problem assocd. with a no. of current implementations of Andersen and Langevin dynamics algorithms. When long simulations are run in many segments, it is sometimes possible to have a repeating sequence of pseudorandom nos. enter the calcn. The authors show that, if the sequence repeats rapidly, the resulting artifacts can quickly denature biomols. and are then easily detectable. However, if the sequence repeats less frequently, the artifacts become subtle and easily overlooked. The authors derive a formula for the underlying cause of artifacts in the case of the Langevin thermostat, and find it vanishes slowly as the inverse square root of the no. of time steps per simulation segment. Numerous examples of simulation artifacts are presented, including dissocn. of a tetrameric protein after 110 ns of dynamics, redns. in at. fluctuations for a small protein in implicit solvent, altered thermodn. properties of a box of water mols., and changes in the transition free energies between dihedral angle conformations. Finally, in the case of strong thermocoupling, we link the obsd. artifacts to previous work in nonlinear dynamics and show that it is possible to drive a 20-residue, implicitly solvated protein into periodic trajectories if the thermostat is not used properly. The authors' findings should help other investigators re-evaluate simulations that may were corrupted and obtain more accurate results.
- 60Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.; Klein, M. L. Comparison of Simple Potential Functions for Simulating Liquid Water J. Chem. Phys. 1983, 79 (2) 926 DOI: 10.1063/1.445869Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3sXksF2htL4%253D&md5=a1161334e381746be8c9b15a5e56f704Comparison of simple potential functions for simulating liquid waterJorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D.; Impey, Roger W.; Klein, Michael L.Journal of Chemical Physics (1983), 79 (2), 926-35CODEN: JCPSA6; ISSN:0021-9606.Classical Monte Carlo simulations were carried out for liq. H2O in the NPT ensemble at 25° and 1 atm using 6 of the simpler intermol. potential functions for the dimer. Comparisons were made with exptl. thermodn. and structural data including the neutron diffraction results of Thiessen and Narten (1982). The computed densities and potential energies agree with expt. except for the original Bernal-Fowler model, which yields an 18% overest. of the d. and poor structural results. The discrepancy may be due to the correction terms needed in processing the neutron data or to an effect uniformly neglected in the computations. Comparisons were made for the self-diffusion coeffs. obtained from mol. dynamics simulations.
- 61Ryckaert, J. P.; Ciccotti, G.; Berendsen, H. J. C. Numerical-Integration of Cartesian Equations of Motion of a System with Constraints - Molecular-Dynamics of N-Alkanes J. Comput. Phys. 1977, 23, 327– 341 DOI: 10.1016/0021-9991(77)90098-5Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2sXktVGhsL4%253D&md5=b4aecddfde149117813a5ea4f5353ce2Numerical integration of the Cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanesRyckaert, Jean Paul; Ciccotti, Giovanni; Berendsen, Herman J. C.Journal of Computational Physics (1977), 23 (3), 327-41CODEN: JCTPAH; ISSN:0021-9991.A numerical algorithm integrating the 3N Cartesian equation of motion of a system of N points subject to holonomic constraints is applied to mol. dynamics simulation of a liq. of 64 butane mols.
- 62Darden, T.; York, D.; Pedersen, L. Particle Mesh Ewald: An N log(N) Method for Ewald Sums in Large Systems J. Chem. Phys. 1993, 98 (12) 10089 DOI: 10.1063/1.464397Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXks1Ohsr0%253D&md5=3c9f230bd01b7b714fd096d4d2e755f6Particle mesh Ewald: an N·log(N) method for Ewald sums in large systemsDarden, Tom; York, Darrin; Pedersen, LeeJournal of Chemical Physics (1993), 98 (12), 10089-92CODEN: JCPSA6; ISSN:0021-9606.An N·log(N) method for evaluating electrostatic energies and forces of large periodic systems is presented. The method is based on interpolation of the reciprocal space Ewald sums and evaluation of the resulting convolution using fast Fourier transforms. Timings and accuracies are presented for three large cryst. ionic systems.
- 63Bennett, C. H. Efficient Estimation of Free Energy Differences from Monte Carlo Data J. Comput. Phys. 1976, 22 (2) 245– 268 DOI: 10.1016/0021-9991(76)90078-4Google ScholarThere is no corresponding record for this reference.
- 64Shirts, M. R.; Chodera, J. D. Statistically Optimal Analysis of Samples from Multiple Equilibrium States J. Chem. Phys. 2008, 129 (12) 124105 DOI: 10.1063/1.2978177Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1WnsL7F&md5=479183e1f45fc58dd7c6e5ef1e73d45dStatistically optimal analysis of samples from multiple equilibrium statesShirts, Michael R.; Chodera, John D.Journal of Chemical Physics (2008), 129 (12), 124105/1-124105/10CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)We present a new estimator for computing free energy differences and thermodn. expectations as well as their uncertainties from samples obtained from multiple equil. states via either simulation or expt. The estimator, which we call the multistate Bennett acceptance ratio estimator (MBAR) because it reduces to the Bennett acceptance ratio estimator (BAR) when only two states are considered, has significant advantages over multiple histogram reweighting methods for combining data from multiple states. It does not require the sampled energy range to be discretized to produce histograms, eliminating bias due to energy binning and significantly reducing the time complexity of computing a soln. to the estg. equations in many cases. Addnl., an est. of the statistical uncertainty is provided for all estd. quantities. In the large sample limit, MBAR is unbiased and has the lowest variance of any known estimator for making use of equil. data collected from multiple states. We illustrate this method by producing a highly precise est. of the potential of mean force for a DNA hairpin system, combining data from multiple optical tweezer measurements under const. force bias. (c) 2008 American Institute of Physics.
- 65O’Boyle, N. M.; Banck, M.; James, C. A.; Morley, C.; Vandermeersch, T.; Hutchison, G. R. Open Babel: An Open Chemical Toolbox J. Cheminf. 2011, 3 (1) 33 DOI: 10.1186/1758-2946-3-33Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVWjurbF&md5=74e4f19b7f87417f916d57f7abcfb761Open Babel: an open chemical toolboxO'Boyle, Noel M.; Banck, Michael; James, Craig A.; Morley, Chris; Vandermeersch, Tim; Hutchison, Geoffrey R.Journal of Cheminformatics (2011), 3 (), 33CODEN: JCOHB3; ISSN:1758-2946. (Chemistry Central Ltd.)Background: A frequent problem in computational modeling is the interconversion of chem. structures between different formats. While std. interchange formats exist (for example, Chem. Markup Language) and de facto stds. have arisen (for example, SMILES format), the need to interconvert formats is a continuing problem due to the multitude of different application areas for chem. data, differences in the data stored by different formats (0D vs. 3D, for example), and competition between software along with a lack of vendor-neutral formats. Results: We discuss, for the first time, Open Babel, an open-source chem. toolbox that speaks the many languages of chem. data. Open Babel version 2.3 interconverts over 110 formats. The need to represent such a wide variety of chem. and mol. data requires a library that implements a wide range of cheminformatics algorithms, from partial charge assignment and aromaticity detection, to bond order perception and canonicalization. We detail the implementation of Open Babel, describe key advances in the 2.3 release, and outline a variety of uses both in terms of software products and scientific research, including applications far beyond simple format interconversion. Conclusions: Open Babel presents a soln. to the proliferation of multiple chem. file formats. In addn., it provides a variety of useful utilities from conformer searching and 2D depiction, to filtering, batch conversion, and substructure and similarity searching. For developers, it can be used as a programming library to handle chem. data in areas such as org. chem., drug design, materials science, and computational chem. It is freely available under an open-source license.
- 66Vanommeslaeghe, K.; MacKerell, A. D. Automation of the CHARMM General Force Field (CGenFF) I: Bond Perception and Atom Typing J. Chem. Inf. Model. 2012, 52 (12) 3144– 3154 DOI: 10.1021/ci300363cGoogle Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1Gns7fL&md5=c6679293f4a2501f2bcadf2020ca1473Automation of the CHARMM General Force Field (CGenFF) I: Bond Perception and Atom TypingVanommeslaeghe, K.; MacKerell, A. D.Journal of Chemical Information and Modeling (2012), 52 (12), 3144-3154CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)Mol. mechanics force fields are widely used in computer-aided drug design for the study of drug-like mols. alone or interacting with biol. systems. In simulations involving biol. macromols., the biol. part is typically represented by a specialized biomol. force field, while the drug is represented by a matching general (org.) force field. In order to apply these general force fields to an arbitrary drug-like mol., functionality for assignment of atom types, parameters, and charges is required. In the present article, which is part I of a series of two, we present the algorithms for bond perception and atom typing for the CHARMM General Force Field (CGenFF). The CGenFF atom typer first assocs. attributes to the atoms and bonds in a mol., such as valence, bond order, and ring membership among others. Of note are a no. of features that are specifically required for CGenFF. This information is then used by the atom typing routine to assign CGenFF atom types based on a programmable decision tree. This allows for straight-forward implementation of CGenFF's complicated atom typing rules and for equally straight-forward updating of the atom typing scheme as the force field grows. The presented atom typer was validated by assigning correct atom types on 477 model compds. including in the training set as well as 126 test-set mols. that were constructed to specifically verify its different components. The program may be utilized via an online implementation at https://www.paramchem.org/.
- 67Cieplak, P.; Cornell, W. D.; Bayly, C.; Kollman, P. A. Application of the Multimolecule and Multiconformational RESP Methodology to Biopolymers: Charge Derivation for DNA, RNA, and Proteins J. Comput. Chem. 1995, 16 (11) 1357– 1377 DOI: 10.1002/jcc.540161106Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXovVKqtrY%253D&md5=27e75f5f3f53d777737661e591e957cdApplication of the multimolecule and multiconformational RESP methodology to biopolymers: charge derivation for DNA, RNA, and proteinsCieplak, Piotr; Cornell, Wendy D.; Bayly, Christopher; Kollman, Peter A.Journal of Computational Chemistry (1995), 16 (11), 1357-77CODEN: JCCHDD; ISSN:0192-8651. (Wiley)The authors present the derivation of charges of ribo- and deoxynucleosides, nucleotides, and peptide fragments using electrostatic potentials obtained from ab initio calcns. with the 6-31G* basis set. For the nucleic acid fragments, the authors used electrostatic potentials of the four deoxyribonucleoside (A, G, C, T) and four ribonucleosides (A, G, C, U) and dimethylphosphate. The charges for the deoxyribose nucleosides and nucleotides are derived using multiple-mol. fitting and restrained electrostatic potential (RESP) fits, with Lagrangian multipliers ensuring a net charge of 0 or. The authors suggest that the preferred approach for deriving charges for nucleosides and nucleotides involves allowing only C1' and H1' of the sugar to vary as the nucleic acid base, with the remainder of sugar and backbone atoms forced to be equiv. For peptide fragments, the authors have combined multiple conformation fitting, previously employed by Williams and Reynolds et al., with the RESP approach to derive charges for blocked dipeptides appropriate for each of the 20 naturally occurring amino acids. Based on the results for Pr amine, the authors suggest that two conformations for each peptide suffice to give charges that represent well the conformationally dependent electrostatic properties of mols., provided that these two conformations contain different values of the dihedral angles that terminate in heteroatoms or hydrogens attached to heteroatoms or hydrogens attached to heteroatoms. In these blocked dipeptide models, it is useful to require equiv. N-H and C=O charges for all amino acids with a given net charge (except proline), and this is accomplished in a straightforward fashion with multiple-mol. fitting. Finally, the application of multiple Lagrangian constraints allows for the derivation of monomeric residues with the appropriate net charge from a chem. blocked version of the residue. The multiple Lagrange constraints also enable charges from two or more mols. to be spliced together in a well-defined fashion. Thus, the combined use of multiple mols., multiple conformations, multiple Lagrangian constraints, and RESP fitting is shown to be a powerful approach to deriving electrostatic charges for biopolymers.
- 68Dupradeau, F.-Y.; Pigache, A.; Zaffran, T.; Savineau, C.; Lelong, R.; Grivel, N.; Lelong, D.; Rosanski, W.; Cieplak, P. The R.E.D. Tools: Advances in RESP and ESP Charge Derivation and Force Field Library Building Phys. Chem. Chem. Phys. 2010, 12 (28) 7821– 7839 DOI: 10.1039/c0cp00111bGoogle Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXosFaqtrk%253D&md5=845cc10ea7ed2f0222361db82bd80e39The R.E.D. tools: advances in RESP and ESP charge derivation and force field library buildingDupradeau, Francois-Yves; Pigache, Adrien; Zaffran, Thomas; Savineau, Corentin; Lelong, Rodolphe; Grivel, Nicolas; Lelong, Dimitri; Rosanski, Wilfried; Cieplak, PiotrPhysical Chemistry Chemical Physics (2010), 12 (28), 7821-7839CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)Deriving at. charges and building a force field library for a new mol. are key steps when developing a force field required for conducting structural and energy-based anal. using mol. mechanics. Derivation of popular RESP charges for a set of residues is a complex and error prone procedure because it depends on numerous input parameters. To overcome these problems, the R.E.D. Tools (RESP and ESP charge Derive, http://q4md-forcefieldtools.org/RED/) have been developed to perform charge derivation in an automatic and straightforward way. The R.E.D. program handles chem. elements up to bromine in the periodic table. It interfaces different quantum mech. programs employed for geometry optimization and computing mol. electrostatic potential(s), and performs charge fitting using the RESP program. By defining tight optimization criteria and by controlling the mol. orientation of each optimized geometry, charge values are reproduced at any computer platform with an accuracy of 0.0001 e. The charges can be fitted using multiple conformations, making them suitable for mol. dynamics simulations. R.E.D. allows also for defining charge constraints during multiple mol. charge fitting, which are used to derive charges for mol. fragments. Finally, R.E.D. incorporates charges into a force field library, readily usable in mol. dynamics computer packages. For complex cases, such as a set of homologous mols. belonging to a common family, an entire force field topol. database is generated. Currently, the at. charges and force field libraries have been developed for more than fifty model systems and stored in the RESP ESP charge DDataBase. Selected results related to non-polarizable charge models are presented and discussed.
- 69Kramer, C.; Gedeck, P.; Meuwly, M. Atomic Multipoles: Electrostatic Potential Fit, Local Reference Axis Systems, and Conformational Dependence J. Comput. Chem. 2012, 33 (20) 1673– 1688 DOI: 10.1002/jcc.22996Google Scholar69https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmtlWjtbw%253D&md5=5d91f01ab9b5dfabf5736a367b2af766Atomic multipoles: Electrostatic potential fit, local reference axis systems, and conformational dependenceKramer, Christian; Gedeck, Peter; Meuwly, MarkusJournal of Computational Chemistry (2012), 33 (20), 1673-1688CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)Currently, all std. force fields for biomol. simulations use point charges to model intermol. electrostatic interactions. This is a fast and simple approach but has deficiencies when the electrostatic potential (ESP) is compared to that from ab initio methods. Here, we show how at. multipoles can be rigorously implemented into common biomol. force fields. For this, a comprehensive set of local ref. axis systems is introduced, which represents a universal soln. for treating atom-centered multipoles for all small org. mols. and proteins. Furthermore, we introduce a new method for fitting at. multipole moments to the quantum mech. derived ESP. This methods yields a 50-90% error redn. compared to both point charges fit to the ESP and multipoles directly calcd. from the ab initio electron d. It is shown that it is necessary to directly fit the multipole moments of conformational ensembles to the ESP. Ignoring the conformational dependence or averaging over parameters from different conformations dramatically deteriorates the results obtained with at. multipole moments, rendering multipoles worse than partial charges. © 2012 Wiley Periodicals, Inc.
- 70Reynolds, C. A.; Essex, J. W.; Richards, W. G. Atomic Charges for Variable Molecular Conformations J. Am. Chem. Soc. 1992, 114 (23) 9075– 9079 DOI: 10.1021/ja00049a045Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XmtFWkt78%253D&md5=47e939c97e4880a8fcb33fed44832b4aAtomic charges for variable molecular conformationsReynolds, Christopher A.; Essex, Jonathan W.; Richards, W. GrahamJournal of the American Chemical Society (1992), 114 (23), 9075-9CODEN: JACSAT; ISSN:0002-7863.The problem of generating high-quality at. charges valid over a range of conformations has been addressed using two related methods which both employ a constrained minimization of the difference between the quantum mech. and classical MEP (mol. electrostatic potential) with respect to the at. charges. The first method involves detg. the MEP and constraining the charges to reproduce the dipole at an alternative geometry. The second method involves detg. the MEP for each conformation of interest and weighting the MEP for each conformation according to the appropriate Boltzmann factor. These methods offer considerable improvement over averaging the charges obtained at each conformation. The improvement in the performance of these multiple conformation MEP derived charges is illustrated by studying the variation of the classical dipole with conformation and comparing the results with those from ab initio calcns. It is proposed that the main use of these multiple conformation MEP derived charges and dipole constrained charges is likely to be in computer simulations where the ability to search conformational space is matched by the ability of the charges to yield the correct electrostatic properties at the conformations of interest. The errors arising from ignoring these effects have been assessed by evaluating the hydration free energy using a continuum method and are found to be significant. The extension of these methods to protein simulations is discussed.
- 71Kramer, C.; Gedeck, P.; Meuwly, M. Multipole-Based Force Fields from Ab Initio Interaction Energies and the Need for Jointly Refitting All Intermolecular Parameters J. Chem. Theory Comput. 2013, 9 (3) 1499– 1511 DOI: 10.1021/ct300888fGoogle Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXis12ltbc%253D&md5=1a5aaefd41c10333f9666cc1853c28aeMultipole-Based Force Fields from ab Initio Interaction Energies and the Need for Jointly Refitting All Intermolecular ParametersKramer, Christian; Gedeck, Peter; Meuwly, MarkusJournal of Chemical Theory and Computation (2013), 9 (3), 1499-1511CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)Distributed at. multipole (MTP) moments promise significant improvements over point charges (PCs) in mol. force fields, as they (a) more realistically reproduce the ab initio electrostatic potential (ESP) and (b) allow to capture anisotropic at. properties such as lone pairs, conjugated systems, and σ holes. The present work focuses on the question of whether multipolar electrostatics instead of PCs in std. force fields leads to quant. improvements over point charges in reproducing intermol. interactions. To this end, the interaction energies of two model systems, benzonitrile (BZN) and formamide (FAM) homodimers, are characterized over a wide range of dimer conformations. It is found that although with MTPs the monomer ab initio ESP can be captured better by about an order of magnitude compared to point charges (PCs), this does not directly translate into better describing ab initio interaction energies compared to PCs. Neither ESP-fitted MTPs nor refitted Lennard-Jones (LJ) parameters alone demonstrate a clear superiority of at. MTPs. We show that only if both electrostatic and LJ parameters are jointly optimized in std., nonpolarizable force fields, at. are MTPs clearly beneficial for reproducing ab initio dimerization energies. After an exhaustive exponent scan, we find that for both BZN and FAM, at. MTPs and a 9-6 LJ potential can reproduce ab initio interaction energies with ∼30% (RMSD 0.13 vs 0.18 kcal/mol) less error than point charges (PCs) and a 12-6 LJ potential. We also find that the improvement due to using MTPs with a 9-6 LJ potential is considerably more pronounced than with a 12-6 LJ potential (≈ 10%; RMSD 0.19 vs. 0.21 kcal/mol).
- 72Wang, L.-P.; Chen, J.; Van Voorhis, T. Systematic Parametrization of Polarizable Force Fields from Quantum Chemistry Data J. Chem. Theory Comput. 2013, 9 (1) 452– 460 DOI: 10.1021/ct300826tGoogle Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslSmtrbO&md5=f6781aa8e4ba50dfb8ca3a0582bafae0Systematic Parametrization of Polarizable Force Fields from Quantum Chemistry DataWang, Lee-Ping; Chen, Jiahao; Van Voorhis, TroyJournal of Chemical Theory and Computation (2013), 9 (1), 452-460CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)We introduce ForceBalance, a method and free software package for systematic force field optimization with the ability to parametrize a wide variety of functional forms using flexible combinations of ref. data. We outline several important challenges in force field development and how they are addressed in ForceBalance, and present an example calcn. where these methods are applied to develop a highly accurate polarizable water model. ForceBalance is available for free download at https://simtk.org/home/forcebalance.
- 73Wang, L.-P.; Martinez, T. J.; Pande, V. S. Building Force Fields: An Automatic, Systematic, and Reproducible Approach J. Phys. Chem. Lett. 2014, 5 (11) 1885– 1891 DOI: 10.1021/jz500737mGoogle Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXnvV2htrs%253D&md5=0b901b4ef8949839df5b5e3e36e38424Building Force Fields: An Automatic, Systematic, and Reproducible ApproachWang, Lee-Ping; Martinez, Todd J.; Pande, Vijay S.Journal of Physical Chemistry Letters (2014), 5 (11), 1885-1891CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)The development of accurate mol. mechanics force fields is a significant challenge that must be addressed for the continued success of mol. simulation. We developed the ForceBalance method to automatically derive accurate force field parameters using flexible combinations of exptl. and theor. ref. data. The method is demonstrated in the parametrization of two rigid water models, yielding new parameter sets (TIP3P-FB and TIP4P-FB) that accurately describe many phys. properties of water.
- 74Mobley, D. L.; Bayly, C. I.; Cooper, M. D.; Shirts, M. R.; Dill, K. A. Small Molecule Hydration Free Energies in Explicit Solvent: An Extensive Test of Fixed-Charge Atomistic Simulations J. Chem. Theory Comput. 2009, 5 (2) 350– 358 DOI: 10.1021/ct800409dGoogle Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXps1Om&md5=df247d489cd56a27d28e842ea2a4c914Small Molecule Hydration Free Energies in Explicit Solvent: An Extensive Test of Fixed-Charge Atomistic SimulationsMobley, David L.; Bayly, Christopher I.; Cooper, Matthew D.; Shirts, Michael R.; Dill, Ken A.Journal of Chemical Theory and Computation (2009), 5 (2), 350-358CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)Using mol. dynamics free energy simulations with TIP3P explicit solvent, the authors compute the hydration free energies of 504 neutral small org. mols. and compare them to expts. They find, first, good general agreement between the simulations and the expts., with an rms error of 1.24 kcal/mol over the whole set (i.e., about 2 kT) and a correlation coeff. of 0.89. Second, they use an automated procedure to identify systematic errors for some classes of compds. and suggest some improvements to the force field. Alkyne hydration free energies are particularly poorly predicted due to problems with a Lennard-Jones well depth and an alternate choice for this well depth largely rectifies the situation. Third, they study the nonpolar component of hydration free energies; i.e., the part that is not due to electrostatics. While repulsive and attractive components of the nonpolar part both scale roughly with surface area (or vol.) of the solute, the total nonpolar free energy does not scale with the solute surface area or vol. because it is a small difference between large components and is dominated by the deviations from the trend. While the methods used here are not new, this is a more extensive test than previous explicit solvent studies, and the size of the test set allows identification of systematic problems with force field parameters for particular classes of compds.
- 75Baker, C. M.; Mackerell, A. D. Polarizability Rescaling and Atom-Based Thole Scaling in the CHARMM Drude Polarizable Force Field for Ethers J. Mol. Model. 2010, 16 (3) 567– 576 DOI: 10.1007/s00894-009-0572-4Google Scholar75https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlslGht7k%253D&md5=7798366fb1fb8eed594bb090a17326e1Polarizability rescaling and atom-based Thole scaling in the CHARMM Drude polarizable force field for ethersBaker, Christopher M.; MacKerell, Alexander D., Jr.Journal of Molecular Modeling (2010), 16 (3), 567-576CODEN: JMMOFK; ISSN:0948-5023. (Springer GmbH)Within the CHARMM polarizable force field based on the classical Drude oscillator, at. polarizabilities are derived via fitting to ab initio calcd. data on isolated gas phase mols., with an empirical scaling factor applied to account for differences between the gas and condensed phases. In the development of polarizable models for the ethers, a polarizability scaling factor of 0.7 was previously applied. While the resulting force field models gave good agreement with a variety of exptl. data, they systematically underestimated the liq. phase dielec. consts. Here, a new CHARMM polarizable model is developed for the ethers, employing a polarizability scaling factor of 0.85 and including atom-based Thole scale factors recently introduced into the CHARMM Drude polarizable force field. The new model offers a significant improvement in the reprodn. of liq. phase dielec. consts., while maintaining the good agreement of the previous model with all other exptl. and quantum mech. data, highlighting the sensitivity of liq. phase properties to the choice of at. polarizability parameters.
- 76Lopes, P. E. M.; Lamoureux, G.; Mackerell, A. D. Polarizable Empirical Force Field for Nitrogen-Containing Heteroaromatic Compounds Based on the Classical Drude Oscillator J. Comput. Chem. 2009, 30 (12) 1821– 1838 DOI: 10.1002/jcc.21183Google ScholarThere is no corresponding record for this reference.
- 77Tukey, J. W. Comparing Individual Means in the Analysis of Variance Biometrics 1949, 5 (2) 99 DOI: 10.2307/3001913Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaH1M%252FltlGgsA%253D%253D&md5=b97aa1acbc9e08776e6d2778f1328fdaComparing individual means in the analysis of varianceTUKEY J WBiometrics (1949), 5 (2), 99-114 ISSN:0006-341X.There is no expanded citation for this reference.
- 78Bradshaw, R. T.; Essex, J. W. Supplementary underlying data for “Evaluating parameterization protocols for hydration free energy calculations with the AMOEBA polarizable force field” http://dx.doi.org/10.5281/zenodo.54959.Google ScholarThere is no corresponding record for this reference.
- 79Wang, L.-P.; Chen, J.; Van Voorhis, T. Systematic Parametrization of Polarizable Force Fields from Quantum Chemistry Data J. Chem. Theory Comput. 2013, 9 (1) 452– 460 DOI: 10.1021/ct300826tGoogle Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslSmtrbO&md5=f6781aa8e4ba50dfb8ca3a0582bafae0Systematic Parametrization of Polarizable Force Fields from Quantum Chemistry DataWang, Lee-Ping; Chen, Jiahao; Van Voorhis, TroyJournal of Chemical Theory and Computation (2013), 9 (1), 452-460CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)We introduce ForceBalance, a method and free software package for systematic force field optimization with the ability to parametrize a wide variety of functional forms using flexible combinations of ref. data. We outline several important challenges in force field development and how they are addressed in ForceBalance, and present an example calcn. where these methods are applied to develop a highly accurate polarizable water model. ForceBalance is available for free download at https://simtk.org/home/forcebalance.
- 80Wang, L.-P.; Head-Gordon, T.; Ponder, J. W.; Ren, P.; Chodera, J. D.; Eastman, P. K.; Martinez, T. J.; Pande, V. S. Systematic Improvement of a Classical Molecular Model of Water J. Phys. Chem. B 2013, 117 (34) 9956– 9972 DOI: 10.1021/jp403802cGoogle Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXptFehtrs%253D&md5=ab76a694e55ac1a916ef2a75ff749673Systematic Improvement of a Classical Molecular Model of WaterWang, Lee-Ping; Head-Gordon, Teresa; Ponder, Jay W.; Ren, Pengyu; Chodera, John D.; Eastman, Peter K.; Martinez, Todd J.; Pande, Vijay S.Journal of Physical Chemistry B (2013), 117 (34), 9956-9972CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)We report the iAMOEBA (inexpensive AMOEBA) classical polarizable water model. The iAMOEBA model uses a direct approxn. to describe electronic polarizability, in which the induced dipoles are detd. directly from the permanent multipole elec. fields and do not interact with one another. The direct approxn. reduces the computational cost relative to a fully self-consistent polarizable model such as AMOEBA. The model is parameterized using ForceBalance, a systematic optimization method that simultaneously utilizes training data from exptl. measurements and high-level ab initio calcns. We show that iAMOEBA is a highly accurate model for water in the solid, liq., and gas phases, with the ability to fully capture the effects of electronic polarization and predict a comprehensive set of water properties beyond the training data set including the phase diagram. The increased accuracy of iAMOEBA over the fully polarizable AMOEBA model demonstrates ForceBalance as a method that allows the researcher to systematically improve empirical models by efficiently utilizing the available data.
- 81Qi, R.; Wang, L.-P.; Wang, Q.; Pande, V. S.; Ren, P. United Polarizable Multipole Water Model for Molecular Mechanics Simulation J. Chem. Phys. 2015, 143 (1) 014504 DOI: 10.1063/1.4923338Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFCjt7vL&md5=b146814ebdf8fe690c22905a32657188United polarizable multipole water model for molecular mechanics simulationQi, Rui; Wang, Lee-Ping; Wang, Qiantao; Pande, Vijay S.; Ren, PengyuJournal of Chemical Physics (2015), 143 (1), 014504/1-014504/12CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)We report the development of a united AMOEBA (uAMOEBA) polarizable water model, which is computationally 3-5 times more efficient than the three-site AMOEBA03 model in mol. dynamics simulations while providing comparable accuracy for gas-phase and liq. properties. In this coarse-grained polarizable water model, both electrostatic (permanent and induced) and van der Waals representations have been reduced to a single site located at the oxygen atom. The permanent charge distribution is described via the mol. dipole and quadrupole moments and the many-body polarization via an isotropic mol. polarizability, all located at the oxygen center. Similarly, a single van der Waals interaction site is used for each water mol. Hydrogen atoms are retained only for the purpose of defining local frames for the mol. multipole moments and intramol. vibrational modes. The parameters have been derived based on a combination of ab initio quantum mech. and exptl. data set contg. gas-phase cluster structures and energies, and liq. thermodn. properties. For validation, addnl. properties including dimer interaction energy, liq. structures, self-diffusion coeff., and shear viscosity have been evaluated. The results demonstrate good transferability from the gas to the liq. phase over a wide range of temps., and from nonpolar to polar environments, due to the presence of mol. polarizability. The water coordination, hydrogen-bonding structure, and dynamic properties given by uAMOEBA are similar to those derived from the all-atom AMOEBA03 model and expts. Thus, the current model is an accurate and efficient alternative for modeling water. (c) 2015 American Institute of Physics.
- 82Bradshaw, R. T.; Essex, J. W. Underlying data for “Evaluating parameterization protocols for hydration free energy calculations with the AMOEBA polarizable force field” http://dx.doi.org/10.5281/zenodo.35586.Google ScholarThere is no corresponding record for this reference.
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Abstract
Figure 1
Figure 1. General AMOEBA parametrization protocol. An initial solute conformer is geometry optimized and subject to distributed multipole analysis to extract a set of atomic multipoles. Multipole parameters are refined by fitting to the molecular electrostatic potential of single or multiple solute conformations. Valence, vdW, and polarizability parameters are assigned based on atom type, while other parameters (e.g., polarization groups) may be assigned either automatically or manually by inspection.
Figure 2
Figure 2. Thermodynamic cycle used in performing alchemical free energy calculations. The cycle has four defined end points: (a) a fully interacting solute in vacuum, (b) a fully interacting solute in water, (c) a discharged and vdW decoupled solute in vacuum, and (d) a discharged and vdW decoupled solute in water. Simulations were separated into three legs: alchemical discharging and vdW decoupling steps in solution, and a discharging step in vacuum. The overall ΔGhyd was calculated as ΔGdischarging,vac – ΔGdecoupling,sol – ΔGdischarging,sol.
Figure 3
Figure 3. Plot of predicted against experimental HFE for parameter set 1. AMOEBA solute parameters were derived using Poltype (38) with modifications outlined in the Supporting Information. Error bars are modeled as standard deviations across three repeat simulations. Solutes 25 and 42 (labeled) had large associated uncertainties due to sampling differences between runs.
Figure 4
Figure 4. Example of possible polarization group definitions for solute L05 (1,2-dimethoxybenzene). A careful choice of polarization groups (right) allows a more realistic response of induced polarization to changes in molecular conformation, e.g., rotation of the two methoxy substituents.
Figure 5
Figure 5. Comparison of parameter sets 1 (blue) and 2 (red) for the subset of substituted benzene solutes. Error bars modeled as standard deviations across three repeat simulations. In set 2, new polarization groups were assigned manually where necessary for each molecule in the subset. Precise polarization groups are detailed in Figure S2.
Figure 6
Figure 6. Comparison of mean molecular ESP around substituted benzene solutes calculated with QM and with AMOEBA parameter sets 2 and 3. Fifty solute structures were extracted from each MD simulation at λ = 1.0, geometry optimized, and subject to QM and AMOEBA ESP calculations. Each point corresponds to a single MD structure, but multiple structures may optimize to similar QM geometries, resulting in irregular horizontal clustering of points. Generating multipoles using a multiconformational fit (parameter set 3, black) results in a much more accurate recreation of QM ESP for conformations visited during a simulation (R2 = 0.97) than a single conformational fit (parameter set 2, blue, and R2 = 0.44).
Figure 7
Figure 7. Comparison of predicted and experimental ΔGhyd for all parameter sets and accompanying linear regressions.
References
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- 2Nicholls, A.; Mobley, D. L.; Guthrie, J. P.; Chodera, J. D.; Bayly, C. I.; Cooper, M. D.; Pande, V. S. Predicting Small-Molecule Solvation Free Energies: An Informal Blind Test for Computational Chemistry J. Med. Chem. 2008, 51 (4) 769– 779 DOI: 10.1021/jm070549+2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXps1GqsQ%253D%253D&md5=6d882cf6dfedacaf4df4204c58a0598ePredicting Small-Molecule Solvation Free Energies: An Informal Blind Test for Computational ChemistryNicholls, Anthony; Mobley, David L.; Guthrie, J. Peter; Chodera, John D.; Pande, Vijay S.Journal of Medicinal Chemistry (2008), 51 (4), 769-779CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Exptl. data on the transfer of small mols. between vacuum and water are relatively sparse. This makes it difficult to assess whether computational methods are truly predictive of this important quantity or merely good at explaining what has been seen. To explore this, a prospective test was performed of two different methods for estg. solvation free energies: an implicit solvent approach based on the Poisson-Boltzmann equation and an explicit solvent approach using alchem. free energy calcns. For a set of 17 small mols., root mean square errors from expt. were between 1.3 and 2.6 kcal/mol, with the explicit solvent free energy approach yielding somewhat greater accuracy but at greater computational expense. Insights from outliers and suggestions for future prospective challenges of this kind are presented.
- 3Shivakumar, D.; Williams, J.; Wu, Y.; Damm, W.; Shelley, J.; Sherman, W. Prediction of Absolute Solvation Free Energies Using Molecular Dynamics Free Energy Perturbation and the OPLS Force Field J. Chem. Theory Comput. 2010, 6 (5) 1509– 1519 DOI: 10.1021/ct900587b3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXkslKhu7g%253D&md5=25d464fb9238e3235e881945c0b50a76Prediction of Absolute Solvation Free Energies using Molecular Dynamics Free Energy Perturbation and the OPLS Force FieldShivakumar, Devleena; Williams, Joshua; Wu, Yujie; Damm, Wolfgang; Shelley, John; Sherman, WoodyJournal of Chemical Theory and Computation (2010), 6 (5), 1509-1519CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)The accurate prediction of protein-ligand binding free energies is a primary objective in computer-aided drug design. The solvation free energy of a small mol. provides a surrogate to the desolvation of the ligand in the thermodn. process of protein-ligand binding. Here, we use explicit solvent mol. dynamics free energy perturbation to predict the abs. solvation free energies of a set of 239 small mols., spanning diverse chem. functional groups commonly found in drugs and drug-like mols. We also compare the performance of abs. solvation free energies obtained using the OPLS_2005 force field with two other commonly used small mol. force fields - general AMBER force field (GAFF) with AM1-BCC charges and CHARMm-MSI with CHelpG charges. Using the OPLS_2005 force field, we obtain high correlation with exptl. solvation free energies (R2 = 0.94) and low av. unsigned errors for a majority of the functional groups compared to AM1-BCC/GAFF or CHelpG/CHARMm-MSI. However, OPLS_2005 has errors of over 1.3 kcal/mol for certain classes of polar compds. We show that predictions on these compd. classes can be improved by using a semiempirical charge assignment method with an implicit bond charge correction.
- 4Martins, S. A.; Sousa, S. F.; Ramos, M. J.; Fernandes, P. A. Prediction of Solvation Free Energies with Thermodynamic Integration Using the General Amber Force Field J. Chem. Theory Comput. 2014, 10 (8) 3570– 3577 DOI: 10.1021/ct500346y4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFyqsL7K&md5=6387491d131a18d6e883151f6cc92089Prediction of Solvation Free Energies with Thermodynamic Integration Using the General Amber Force FieldMartins, Silvia A.; Sousa, Sergio F.; Ramos, Maria Joao; Fernandes, Pedro A.Journal of Chemical Theory and Computation (2014), 10 (8), 3570-3577CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)Computer-aided drug design (CADD) techniques can be very effective in reducing costs and speeding up drug discovery. The detn. of binding and solvation free energies is pivotal for this process and is, therefore, the subject of many studies. In this work, the solvation free energy change (ΔΔGsolv) for a total of 92 transformations in small mols. was predicted using Thermodn. Integration (TI). The aim was to compare exptl. and calcd. solvation free energies for typical and prime addns. considered in drug optimizations, analyzing trends, and optimizing a TI protocol. The results showed a good agreement between exptl. and predicted values, with an overestimation of the predicted values for CH3, halogens, and NH2, as well as an underestimation for CONH2, but all fall within ±1 kcal/mol. NO2 addn. showed a larger and systematic underestimation of the predicted ΔΔGsolv, indicating the need for special attention in these cases. For small mols., if no exptl. data is available, using TI as a theor. strategy thus appears to be a suitable choice in CADD. It provides a good compromise between time and accuracy.
- 5Hansen, N.; van Gunsteren, W. F. Practical Aspects of Free-Energy Calculations: A Review J. Chem. Theory Comput. 2014, 10 (7) 2632– 2647 DOI: 10.1021/ct500161f5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXotlWjs7k%253D&md5=096fd11727692a87b0884e50bcb4a5e3Practical Aspects of Free-Energy Calculations: A ReviewHansen, Niels; van Gunsteren, Wilfred F.Journal of Chemical Theory and Computation (2014), 10 (7), 2632-2647CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)A review. Free-energy calcns. in the framework of classical mol. dynamics simulations are nowadays used in a wide range of research areas including solvation thermodn., mol. recognition, and protein folding. The basic components of a free-energy calcn., i.e., a suitable model Hamiltonian, a sampling protocol, and an estimator for the free energy, are independent of the specific application. However, the attention that one has to pay to these components depends considerably on the specific application. Here, we review six different areas of application and discuss the relative importance of the three main components to provide the reader with an organigram and to make nonexperts aware of the many pitfalls present in free energy calcns.
- 6Jorgensen, W. L. The Many Roles of Computation in Drug Discovery Science 2004, 303 (5665) 1813– 1818 DOI: 10.1126/science.10963616https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXitFehu7w%253D&md5=77b2fac63e750ca7cdc7e4f35654549aThe Many Roles of Computation in Drug DiscoveryJorgensen, William L.Science (Washington, DC, United States) (2004), 303 (5665), 1813-1818CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)A review. An overview is given on the diverse uses of computational chem. in drug discovery. Particular emphasis is placed on virtual screening, de novo design, evaluation of drug-likeness, and advanced methods for detg. protein-ligand binding.
- 7Kelly, C. P.; Cramer, C. J.; Truhlar, D. G. SM6: A Density Functional Theory Continuum Solvation Model for Calculating Aqueous Solvation Free Energies of Neutrals, Ions, and Solute–Water Clusters J. Chem. Theory Comput. 2005, 1 (6) 1133– 1152 DOI: 10.1021/ct050164b7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFegsrbE&md5=7be83d42a3375786978c86eb50600f0eSM6: A Density Functional Theory Continuum Solvation Model for Calculating Aqueous Solvation Free Energies of Neutrals, Ions, and Solute-Water ClustersKelly, Casey P.; Cramer, Christopher J.; Truhlar, Donald G.Journal of Chemical Theory and Computation (2005), 1 (6), 1133-1152CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)A new charge model, called Charge Model 4 (CM4), and a new continuum solvent model, called Solvation Model 6 (SM6), are presented. Using a database of aq. solvation free energies for 273 neutrals, 112 ions, and 31 ion-water clusters, parameter sets for the mPW0 hybrid d. functional of Adamo and Barone (Adamo, C.; Barone, V. J. Chem. Phys. 1998, 108, 664-675) were optimized for use with the following four basis sets: MIDI!6D, 6-31G(d), 6-31+G(d), and 6-31+G(d,p). SM6 separates the observable aq. solvation free energy into two different components: one arising from long-range bulk electrostatic effects and a second from short-range interactions between the solute and solvent mols. in the first solvation shell. This partition of the observable solvation free energy allows SM6 to effectively model a wide range of solutes. For the 273 neutral solutes in the test set, SM6 achieves an av. error of ∼0.50 kcal/mol in the aq. solvation free energies. For solutes, esp. ions, that have highly concd. regions of charge d., adding an explicit water mol. to the calcn. significantly improves the performance of SM6 for predicting solvation free energies. The performance of SM6 was tested against several other continuum models, including SM5.43R and several different implementations of the Polarizable Continuum Model (PCM). For both neutral and ionic solutes, SM6 outperforms all of the models against which it was tested. Also, SM6 is the only model (except for one with an av. error 3.4 times larger) that improves when an explicit solvent mol. is added to solutes with concd. charge densities. Thus, in SM6, unlike the other continuum models tested here, adding one or more explicit solvent mol. to the calcn. is an effective strategy for improving the prediction of the aq. solvation free energies of solutes with strong local solute-solvent interactions. This is important, because local solute-solvent interactions are not specifically accounted for by bulk electrostatics, but modeling these interactions correctly is important for predicting the aq. solvation free energies of certain solutes. Finally, SM6 retains its accuracy when used in conjunction with the B3LYP and B3PW91 functionals, and in fact the solvation parameters obtained with a given basis set may be used with any good d. functional or fraction of Hartree-Fock exchange.
- 8Marenich, A. V.; Olson, R. M.; Kelly, C. P.; Cramer, C. J.; Truhlar, D. G. Self-Consistent Reaction Field Model for Aqueous and Nonaqueous Solutions Based on Accurate Polarized Partial Charges J. Chem. Theory Comput. 2007, 3 (6) 2011– 2033 DOI: 10.1021/ct70014188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFSqsrbJ&md5=002518393e08359394f671a73ca9a548Self-Consistent Reaction Field Model for Aqueous and Nonaqueous Solutions Based on Accurate Polarized Partial ChargesMarenich, Aleksandr V.; Olson, Ryan M.; Kelly, Casey P.; Cramer, Christopher J.; Truhlar, Donald G.Journal of Chemical Theory and Computation (2007), 3 (6), 2011-2033CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)A new universal continuum solvation model (where "universal" denotes applicable to all solvents), called SM8, is presented. It is an implicit solvation model, also called a continuum solvation model, and it improves on earlier SMx universal solvation models by including free energies of solvation of ions in nonaq. media in the parametrization. SM8 is applicable to any charged or uncharged solute composed of H, C, N, O, F, Si, P, S, Cl, and/or Br in any solvent or liq. medium for which a few key descriptors are known, in particular dielec. const., refractive index, bulk surface tension, and acidity and basicity parameters. It does not require the user to assign mol.-mechanics types to an atom or group; all parameters are unique and continuous functions of geometry. It may be used with any level of electronic structure theory as long as accurate partial charges can be computed for that level of theory; the authors recommend using it with self-consistently polarized Charge Model 4 or other self-consistently polarized class IV charges, in which case analytic gradients are available. The model separates the observable solvation free energy into two components: the long-range bulk electrostatic contribution arising from a self-consistent reaction field treatment using the generalized Born approxn. for electrostatics is augmented by the non-bulk-electrostatic contribution arising from short-range interactions between the solute and solvent mols. in the first solvation shell. The cavities for the bulk electrostatics calcn. are defined by superpositions of nuclear-centered spheres whose sizes are detd. by intrinsic at. Coulomb radii. The radii used for aq. soln. are the same as parametrized previously for the SM6 aq. solvation model, and the radii for nonaq. soln. are parametrized by a training set of 220 bare ions and 21 clustered ions in acetonitrile, methanol, and DMSO. The non-bulk-electrostatic terms are proportional to the solvent-accessible surface areas of the atoms of the solute and have been parametrized using solvation free energies for a training set of 2346 solvation free energies for 318 neutral solutes in 90 nonaq. solvents and water and 143 transfer free energies for 93 neutral solutes between water and 15 org. solvents. The model is tested with three d. functionals and with four basis sets: 6-31+G(d,p), 6-31+G(d), 6-31G(d), and MIDI!6D. The SM8 model achieves mean unsigned errors of 0.5-0.8 kcal/mol in the solvation free energies of tested neutrals and mean unsigned errors of 2.2-7.0 kcal/mol for ions. The model outperforms the earlier SM5.43R and SM7 universal solvation models as well as the default Polarizable Continuum Model (PCM) implemented in Gaussian 98/03, the Conductor-like PCM as implemented in GAMESS, Jaguar's continuum model based on numerical soln. of the Poisson equation, and the GCOSMO model implemented in NWChem.
- 9Mobley, D. L.; Guthrie, J. P. FreeSolv: A Database of Experimental and Calculated Hydration Free Energies, with Input Files J. Comput.-Aided Mol. Des. 2014, 28 (7) 711– 720 DOI: 10.1007/s10822-014-9747-x9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXpvVeitb0%253D&md5=23d3152ee50654206bac75a6e4492101FreeSolv: a database of experimental and calculated hydration free energies, with input filesMobley, David L.; Guthrie, J. PeterJournal of Computer-Aided Molecular Design (2014), 28 (7), 711-720CODEN: JCADEQ; ISSN:0920-654X. (Springer)This work provides a curated database of exptl. and calcd. hydration free energies for small neutral mols. in water, along with mol. structures, input files, refs., and annotations. We call this the Free Solvation Database, or FreeSolv. Exptl. values were taken from prior literature and will continue to be curated, with updated exptl. refs. and data added as they become available. Calcd. values are based on alchem. free energy calcns. using mol. dynamics simulations. These used the GAFF small mol. force field in TIP3P water with AM1-BCC charges. Values were calcd. with the GROMACS simulation package, with full details given in refs. cited within the database itself. This database builds in part on a previous, 504-mol. database contg. similar information. However, addnl. curation of both exptl. data and calcd. values has been done here, and the total no. of mols. is now up to 643. Addnl. information is now included in the database, such as SMILES strings, PubChem compd. IDs, accurate ref. DOIs, and others. One version of the database is provided in the Supporting Information of this article, but as ongoing updates are envisioned, the database is now versioned and hosted online. In addn. to providing the database, this work describes its construction process. The database is available free-of-charge via http://www.escholarship.org/uc/item/6sd403pz.
- 10Guthrie, J. P. A Blind Challenge for Computational Solvation Free Energies: Introduction and Overview J. Phys. Chem. B 2009, 113 (14) 4501– 4507 DOI: 10.1021/jp806724u10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjslelsLo%253D&md5=3a14054823eaed5775309d268173f59dA Blind Challenge for Computational Solvation Free Energies: Introduction and OverviewGuthrie, J. PeterJournal of Physical Chemistry B (2009), 113 (14), 4501-4507CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)A review. The accompanying set of papers arose from a recent blind challenge to computational solvation energies. The challenge was based on a set of 63 drug-like mols. for which solvation energies could be extd. from the literature. While the results are encouraging, there is still need for improvement.
- 11Geballe, M. T.; Skillman, A. G.; Nicholls, A.; Guthrie, J. P.; Taylor, P. J. The SAMPL2 Blind Prediction Challenge: Introduction and Overview J. Comput.-Aided Mol. Des. 2010, 24 (4) 259– 279 DOI: 10.1007/s10822-010-9350-811https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmsFSmsb8%253D&md5=bab4eefa9886bf8b06c6f3cd02e9acd1The SAMPL2 blind prediction challenge: introduction and overviewGeballe, Matthew T.; Skillman, A. Geoffrey; Nicholls, Anthony; Guthrie, J. Peter; Taylor, Peter J.Journal of Computer-Aided Molecular Design (2010), 24 (4), 259-279CODEN: JCADEQ; ISSN:0920-654X. (Springer)A review. The interactions between a mol. and the aq. environment underpin any process that occurs in soln., from simple chem. reactions to protein-ligand binding to protein aggregation. Fundamental measures of the interaction between mol. and aq. phase, such as the transfer energy between gas phase and water or the energetic difference between two tautomers of a mol. in soln., remain nontrivial to predict accurately using current computational methods. SAMPL2 represents the third annual blind prediction of transfer energies, and the first time tautomer ratios were included in the challenge. Over 60 sets of predictions were submitted, and each participant also attempted to est. the error in their predictions, a task that proved difficult for most. The results of this blind assessment of the state of the field for transfer energy and tautomer ratio prediction both indicate where the field is performing well and point out flaws in current methods.
- 12Geballe, M. T.; Guthrie, J. P. The SAMPL3 Blind Prediction Challenge: Transfer Energy Overview J. Comput.-Aided Mol. Des. 2012, 26 (5) 489– 496 DOI: 10.1007/s10822-012-9568-8There is no corresponding record for this reference.
- 13Guthrie, J. P. SAMPL4, a Blind Challenge for Computational Solvation Free Energies: The Compounds Considered J. Comput.-Aided Mol. Des. 2014, 28 (3) 151– 168 DOI: 10.1007/s10822-014-9738-yThere is no corresponding record for this reference.
- 14Mobley, D.; Wymer, K.; Lim, N.; Guthrie, J. P. Blind Prediction of Solvation Free Energies from the SAMPL4 Challenge J. Comput.-Aided Mol. Des. 2014, 28 (3) 135– 150 DOI: 10.1007/s10822-014-9718-214https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjvVyqu74%253D&md5=4b67de6fdc5fa04d58d10e3d5a1692e5Blind prediction of solvation free energies from the SAMPL4 challengeMobley, David L.; Wymer, Karisa L.; Lim, Nathan M.; Guthrie, J. PeterJournal of Computer-Aided Molecular Design (2014), 28 (3), 135-150CODEN: JCADEQ; ISSN:0920-654X. (Springer)Here, we give an overview of the small mol. hydration portion of the SAMPL4 challenge, which focused on predicting hydration free energies for a series of 47 small mols. These gas-to-water transfer free energies have in the past proven a valuable test of a variety of computational methods and force fields. Here, in contrast to some previous SAMPL challenges, we find a relatively wide range of methods perform quite well on this test set, with RMS errors in the 1.2 kcal/mol range for several of the best performing methods. Top-performers included a quantum mech. approach with continuum solvent models and functional group corrections, alchem. mol. dynamics simulations with a classical all-atom force field, and a single-conformation Poisson-Boltzmann approach. While 1.2 kcal/mol is still a significant error, exptl. hydration free energies covered a range of nearly 20 kcal/mol, so methods typically showed substantial predictive power. Here, a substantial new focus was on evaluation of error ests., as predicting when a computational prediction is reliable vs. unreliable has considerable practical value. We found, however, that in many cases errors are substantially underestimated, and that typically little effort has been invested in estg. likely error. We believe this is an important area for further research.
- 15SAMPL5 https://drugdesigndata.org/about/sampl5 (accessed Dec 16, 2015) .There is no corresponding record for this reference.
- 16Ponder, J. W.; Wu, C. J.; Ren, P. Y.; Pande, V. S.; Chodera, J. D.; Schnieders, M. J.; Haque, I.; Mobley, D. L.; Lambrecht, D. S.; DiStasio, R. A.; Head-Gordon, M.; Clark, G. N. I.; Johnson, M. E.; Head-Gordon, T. Current Status of the AMOEBA Polarizable Force Field J. Phys. Chem. B 2010, 114 (8) 2549– 2564 DOI: 10.1021/jp910674d16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1Gmt7s%253D&md5=c2a2addabc2e6d3f2dc4b4db878bd282Current Status of the AMOEBA Polarizable Force FieldPonder, Jay W.; Wu, Chuanjie; Ren, Pengyu; Pande, Vijay S.; Chodera, John D.; Schnieders, Michael J.; Haque, Imran; Mobley, David L.; Lambrecht, Daniel S.; Di Stasio, Robert A.; Head-Gordon, Martin; Clark, Gary N. I.; Johnson, Margaret E.; Head-Gordon, TeresaJournal of Physical Chemistry B (2010), 114 (8), 2549-2564CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)A review. Mol. force fields have been approaching a generational transition over the past several years, moving away from well-established and well-tuned, but intrinsically limited, fixed point charge models toward more intricate and expensive polarizable models that should allow more accurate description of mol. properties. The recently introduced AMOEBA force field is a leading publicly available example of this next generation of theor. model, but to date, it has only received relatively limited validation, which we address here. We show that the AMOEBA force field is in fact a significant improvement over fixed charge models for small mol. structural and thermodn. observables in particular, although further fine-tuning is necessary to describe solvation free energies of drug-like small mols., dynamical properties away from ambient conditions, and possible improvements in arom. interactions. State of the art electronic structure calcns. reveal generally very good agreement with AMOEBA for demanding problems such as relative conformational energies of the alanine tetrapeptide and isomers of water sulfate complexes. AMOEBA is shown to be esp. successful on protein-ligand binding and computational X-ray crystallog. where polarization and accurate electrostatics are crit.
- 17Demerdash, O.; Yap, E.-H.; Head-Gordon, T. Advanced Potential Energy Surfaces for Condensed Phase Simulation Annu. Rev. Phys. Chem. 2014, 65 (1) 149– 174 DOI: 10.1146/annurev-physchem-040412-110040There is no corresponding record for this reference.
- 18Shi, Y.; Ren, P.; Schnieders, M.; Piquemal, J.-P. Polarizable Force Fields for Biomolecular Modeling. In Reviews in Computational Chemistry; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2015; Vol. 28, pp 51– 86.There is no corresponding record for this reference.
- 19Huang, J.; Lopes, P. E. M.; Roux, B.; MacKerell, A. D. Recent Advances in Polarizable Force Fields for Macromolecules: Microsecond Simulations of Proteins Using the Classical Drude Oscillator Model J. Phys. Chem. Lett. 2014, 5 (18) 3144– 3150 DOI: 10.1021/jz501315h19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVeksLbO&md5=4ed2a9179936991094aaa597e80b2a61Recent advances in polarizable force fields for macromolecules: Microsecond simulations of proteins using the classical Drude oscillator modelHuang, Jing; Lopes, Pedro E. M.; Roux, Benoit; MacKerell, Alexander D.Journal of Physical Chemistry Letters (2014), 5 (18), 3144-3150CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)A review. The authors summarize recent efforts to include the explicit treatment of induced electronic polarization in biomol. force fields. Methods used to treat polarizability, including the induced dipole, fluctuating charge, and classical Drude oscillator models, are presented, including recent advances in force fields using those methods. This is followed by recent results obtained with the Drude model, including microsecond mol. dynamics (MD) simulations of multiple proteins in explicit solvent. The results show significant variability of backbone and side-chain dipole moments as a function of environment, including significant changes during individual simulations. Dipole moments of water in the vicinity of the proteins reveal small but systematic changes, with the direction of the changes dependent on the environment. Analyses of the full proteins show that the polarizable Drude model leads to larger values of the dielec. const. of the protein interior, esp. in the case of hydrophobic regions. These results indicate that the inclusion of explicit electronic polarizability leads to significant differences in the phys. forces affecting the structure and dynamics of proteins, which can be investigated in a computationally tractable fashion in the context of the Drude model.
- 20Baker, C. M. Polarizable Force Fields for Molecular Dynamics Simulations of Biomolecules Wiley Interdiscip. Rev. Comput. Mol. Sci. 2015, 5 (2) 241– 254 DOI: 10.1002/wcms.121520https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXisF2nu7s%253D&md5=acffeab784e0876f9641f0874d87020fPolarizable force fields for molecular dynamics simulations of biomoleculesBaker, Christopher M.Wiley Interdisciplinary Reviews: Computational Molecular Science (2015), 5 (2), 241-254CODEN: WIRCAH; ISSN:1759-0884. (Wiley-Blackwell)Mol. dynamics simulations are well established for the study of biomol. systems. Within these simulations, energy functions known as force fields are used to det. the forces acting on atoms and mols. While these force fields have been very successful, they contain a no. of approxns., included to overcome limitations in computing power. One of the most important of these approxns. is the omission of polarizability, the process by which the charge distribution in a mol. changes in response to its environment. Since polarizability is known to be important in many biochem. situations, and since advances in computer hardware have reduced the need for approxns. within force fields, there is major interest in the use of force fields that include an explicit representation of polarizability. As such, a no. of polarizable force fields have been under development: these have been largely exptl., and their use restricted to specialized researchers. This situation is now changing. Parameters for fully optimized polarizable force fields are being published, and assocd. code incorporated into std. simulation software. Simulations on the hundred-nanosecond timescale are being reported, and are now within reach of all simulation scientists. In this overview, I examine the polarizable force fields available for the simulation of biomols., the systems to which they have been applied, and the benefits and challenges that polarizability can bring. In considering future directions for development of polarizable force fields, I examine lessons learnt from non-polarizable force fields, and highlight issues that remain to be addressed. WIREs Comput Mol Sci 2015, 5:241-254. doi: 10.1002/wcms.1215. Conflict of interest: The author has declared no conflicts of interest for this article.
- 21Ren, P. Y.; Wu, C.; Ponder, J. W. Polarizable Atomic Multipole-Based Molecular Mechanics for Organic Molecules J. Chem. Theory Comput. 2011, 7 (10) 3143– 3161 DOI: 10.1021/ct200304d21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFGgtrbN&md5=04b55d33dfd8770899a5d2300c9b6cf9Polarizable Atomic Multipole-Based Molecular Mechanics for Organic MoleculesRen, Pengyu; Wu, Chuanjie; Ponder, Jay W.Journal of Chemical Theory and Computation (2011), 7 (10), 3143-3161CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)An empirical potential based on permanent at. multipoles and at. induced dipoles is reported for alkanes, alcs., amines, sulfides, aldehydes, carboxylic acids, amides, aroms., and other small org. mols. Permanent at. multipole moments through quadrupole moments were derived from gas phase ab initio MO calcns. The van der Waals parameters are obtained by fitting to gas phase homodimer QM energies and structures, as well as exptl. densities and heats of vaporization of neat liqs. As a validation, the hydrogen bonding energies and structures of gas phase heterodimers with water are evaluated using the resulting potential. For 32 homo- and heterodimers, the assocn. energy agrees with ab initio results to within 0.4 kcal/mol. The root-mean-square deviation of the hydrogen bond distance from QM optimized geometry is <0.06 Å. Liq. self-diffusion and static dielec. consts. computed from a mol. dynamics simulation are consistent with exptl. values. The force field is also used to compute the solvation free energy of 27 compds. not included in the parametrization process, with a root-mean-square error of 0.69 kcal/mol. The results obtained in this study suggest that the AMOEBA force field performs well across different environments and phases. The key algorithms involved in the electrostatic model and a protocol for developing parameters are detailed to facilitate extension to addnl. mol. systems.
- 22Baker, C. M.; Lopes, P. E. M.; Zhu, X.; Roux, B.; Mackerell, A. D. Accurate Calculation of Hydration Free Energies Using Pair-Specific Lennard-Jones Parameters in the CHARMM Drude Polarizable Force Field J. Chem. Theory Comput. 2010, 6 (4) 1181– 1198 DOI: 10.1021/ct900577322https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXisFGmsbY%253D&md5=2118f6899e5328a95e08bd4e41411a2fAccurate Calculation of Hydration Free Energies using Pair-Specific Lennard-Jones Parameters in the CHARMM Drude Polarizable Force FieldBaker, Christopher M.; Lopes, Pedro E. M.; Zhu, Xiao; Roux, Benoit; MacKerell, Alexander D.Journal of Chemical Theory and Computation (2010), 6 (4), 1181-1198CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)Lennard-Jones (LJ) parameters for a variety of model compds. have previously been optimized within the CHARMM Drude polarizable force field to reproduce accurately pure liq. phase thermodn. properties as well as addnl. target data. While the polarizable force field resulting from this optimization procedure has been shown to satisfactorily reproduce a wide range of exptl. ref. data across numerous series of small mols., a slight but systematic overestimate of the hydration free energies has also been noted. Here, the reprodn. of exptl. hydration free energies is greatly improved by the introduction of pair-specific LJ parameters between solute heavy atoms and water oxygen atoms that override the std. LJ parameters obtained from combining rules. The changes are small and a systematic protocol is developed for the optimization of pair-specific LJ parameters and applied to the development of pair-specific LJ parameters for alkanes, alcs., and ethers. The resulting parameters not only yield hydration free energies in good agreement with exptl. values, but also provide a framework upon which other pair-specific LJ parameters can be added as new compds. are parametrized within the CHARMM Drude polarizable force field. Detailed anal. of the contributions to the hydration free energies reveals that the dispersion interaction is the main source of the systematic errors in the hydration free energies. This information suggests that the systematic error may result from problems with the LJ combining rules and is combined with anal. of the pair-specific LJ parameters obtained in this work to identify a preliminary improved combining rule.
- 23Zhong, Y.; Patel, S. Nonadditive Empirical Force Fields for Short-Chain Linear Alcohols: Methanol to Butanol. Hydration Free Energetics and Kirkwood-Buff Analysis Using Charge Equilibration Models J. Phys. Chem. B 2010, 114 (34) 11076– 11092 DOI: 10.1021/jp101597rThere is no corresponding record for this reference.
- 24Zhang, J.; Yang, W.; Piquemal, J.-P.; Ren, P. Modeling Structural Coordination and Ligand Binding in Zinc Proteins with a Polarizable Potential J. Chem. Theory Comput. 2012, 8 (4) 1314– 1324 DOI: 10.1021/ct200812y24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XitFKkt7g%253D&md5=d96c6b59f1ab977b69dda9f57d31b54aModeling Structural Coordination and Ligand Binding in Zinc Proteins with a Polarizable PotentialZhang, Jiajing; Yang, Wei; Piquemal, Jean-Philip; Ren, PengyuJournal of Chemical Theory and Computation (2012), 8 (4), 1314-1324CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)As the second most abundant cation in the human body, zinc is vital for the structures and functions of many proteins. Zinc-contg. matrix metalloproteinases (MMPs) have been widely investigated as potential drug targets in a range of diseases ranging from cardiovascular disorders to cancers. However, it remains a challenge in theor. studies to treat zinc in proteins with classical mechanics. In this study, we examd. Zn2+ coordination with org. compds. and protein side chains using a polarizable at. multipole-based electrostatic model. We find that the polarization effect plays a detg. role in Zn2+ coordination geometry in both matrix metalloproteinase (MMP) complexes and zinc-finger proteins. In addn., the relative binding free energies of selected inhibitors binding with MMP13 have been estd. and compared with exptl. results. While not directly interacting with the small mol. inhibitors, the permanent and polarizing field of Zn2+ exerts a strong influence on the relative affinities of the ligands. The simulation results also reveal that the polarization effect on binding is ligand-dependent and thus difficult to incorporate into fixed-charge models implicitly.
- 25Fried, S. D.; Wang, L.-P.; Boxer, S. G.; Ren, P.; Pande, V. S. Calculations of the Electric Fields in Liquid Solutions J. Phys. Chem. B 2013, 117 (50) 16236– 16248 DOI: 10.1021/jp410720y25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvV2ku7%252FO&md5=6d31f2009947b9792643f3abaafe5a60Calculations of the Electric Fields in Liquid SolutionsFried, Stephen D.; Wang, Lee-Ping; Boxer, Steven G.; Ren, Pengyu; Pande, Vijay S.Journal of Physical Chemistry B (2013), 117 (50), 16236-16248CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)The elec. field created by a condensed-phase environment is a powerful and convenient descriptor for intermol. interactions. Not only does it provide a unifying language to compare many different types of interactions, but it also possesses clear connections to exptl. observables, such as vibrational Stark effects. We calc. here the elec. fields experienced by a vibrational chromophore (the carbonyl group of acetophenone) in an array of solvents of diverse polarities using mol. dynamics simulations with the AMOEBA polarizable force field. The mean and variance of the calcd. elec. fields correlate well with solvent-induced frequency shifts and band broadening, suggesting Stark effects as the underlying mechanism of these key soln.-phase spectral effects. Compared to fixed-charge and continuum models, AMOEBA was the only model examd. that could describe nonpolar, polar, and hydrogen bonding environments in a consistent fashion. Nevertheless, we found that fixed-charge force fields and continuum models were able to replicate some results of the polarizable simulations accurately, allowing us to clearly identify which properties and situations require explicit polarization and/or atomistic representations to be modeled properly, and to identify for which properties and situations simpler models are sufficient. We also discuss the ramifications of these results for modeling electrostatics in complex environments, such as proteins.
- 26Kuster, D. J.; Liu, C.; Fang, Z.; Ponder, J. W.; Marshall, G. R. High-Resolution Crystal Structures of Protein Helices Reconciled with Three-Centered Hydrogen Bonds and Multipole Electrostatics PLoS One 2015, 10 (4) e0123146 DOI: 10.1371/journal.pone.0123146There is no corresponding record for this reference.
- 27El Hage, K.; Piquemal, J.-P.; Hobaika, Z.; Maroun, R. G.; Gresh, N. Substituent-Modulated Affinities of Halobenzene Derivatives to the HIV-1 Integrase Recognition Site. Analyses of the Interaction Energies by Parallel Quantum Chemical and Polarizable Molecular Mechanics J. Phys. Chem. A 2014, 118 (41) 9772– 9782 DOI: 10.1021/jp5079899There is no corresponding record for this reference.
- 28MacDermaid, C. M.; Kaminski, G. A. Electrostatic Polarization Is Crucial for Reproducing pKa Shifts of Carboxylic Residues in Turkey Ovomucoid Third Domain J. Phys. Chem. B 2007, 111 (30) 9036– 9044 DOI: 10.1021/jp071284d28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmvFejtrg%253D&md5=9a6c4554ef7105b7a28d6e736df0325eElectrostatic Polarization Is Crucial for Reproducing pKa Shifts of Carboxylic Residues in Turkey Ovomucoid Third DomainMacDermaid, Christopher M.; Kaminski, George A.Journal of Physical Chemistry B (2007), 111 (30), 9036-9044CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)We have computed pKa shifts for carboxylic residues of the serine protease inhibitor turkey ovomucoid third domain (residues Asp7, Glu10, Glu19, Asp27, and Glu43). Both polarizable and nonpolarizable empirical force fields were employed. Hydration was represented by the surface generalized Born and Poisson-Boltzmann continuum model. The calcns. were carried out in the most phys. straightforward fashion, by directly comparing energies of the protonated and deprotonated protein forms, without any addnl. parameter fitting or adjustment. Our studies have demonstrated that (i) the Poisson-Boltzmann solvation model is more than adequate in reproducing pKa shifts, most likely due to its intrinsically many-body formalism; (ii) explicit treatment of electrostatic polarization included in our polarizable force field (PFF) calcns. appears to be crucial in reproducing the acidity const. shifts. The av. error of the PFF results was found to be as low as 0.58 pKa units, with the best fixed-charges av. deviation being 3.28 units. Therefore, the pKa shifts phenomena and the governing electrostatics are clearly many-body controlled in their intrinsic nature; (iii) our results confirm previously reported conclusions that pKa shifts for protein residues are controlled by the immediate environment of the residues in question, as opposed to long-range interactions in proteins. We are confident that our confirmation of the importance of explicit inclusion of polarization in empirical force fields for protein studies will be useful far beyond the immediate goal of accurate calcn. of acidity consts.
- 29Lemkul, J. A.; Savelyev, A.; MacKerell, A. D. Induced Polarization Influences the Fundamental Forces in DNA Base Flipping J. Phys. Chem. Lett. 2014, 5 (12) 2077– 2083 DOI: 10.1021/jz500951729https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXosl2qtr0%253D&md5=423e8ead8524a0af9ba630d967c4fe46Induced polarization influences the fundamental forces in DNA base flippingLemkul, Justin A.; Savelyev, Alexey; MacKerell, Alexander D.Journal of Physical Chemistry Letters (2014), 5 (12), 2077-2083CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)Base flipping in DNA is an important process involved in genomic repair and epigenetic control of gene expression. The driving forces for these processes are not fully understood, esp. in the context of the underlying dynamics of the DNA and solvent effects. Here, the authors studied double-stranded DNA oligomers that were previously characterized by imino proton exchange NMR using both additive and polarizable force fields. The results highlighted the importance of induced polarization on the base flipping process, yielding near-quant. agreement with exptl. measurements of the equil. between the base-paired and flipped states. Further, these simulations allow the authors to quantify for the 1st time the energetic implications of polarization on the flipping pathway. Free energy barriers to base flipping were reduced by changes in dipole moments of both the flipped bases that favored solvation of the bases in the open state and water mols. adjacent to the flipping base.
- 30Huang, J.; MacKerell, A. D. Induction of Peptide Bond Dipoles Drives Cooperative Helix Formation in the (AAQAA)3 Peptide Biophys. J. 2014, 107 (4) 991– 997 DOI: 10.1016/j.bpj.2014.06.03830https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsValtbfI&md5=ac957b9b4ba06b568cbf922ff399d3e4Induction of Peptide Bond Dipoles Drives Cooperative Helix Formation in the (AAQAA)3 PeptideHuang, Jing; MacKerell, Alexander D. Jr.Biophysical Journal (2014), 107 (4), 991-997CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)Cooperativity is a central feature in the formation of secondary structures in proteins. However, the driving forces behind this cooperativity are poorly understood. The present work shows that the cooperativity of helix formation in the acetyl-(AAQAA)3-NH2 peptide is significantly enhanced using an empirical force field that explicitly includes the treatment of electronic polarizability. Polarizable simulations yield helical content consistent with exptl. measurements and indicate that the dependence of helical content on temp. is improved over additive models, though further sampling is required to fully validate this conclusion. Cooperativity is indicated by the peptide sampling either the coiled state or long helixes with relatively low populations of short helixes. The cooperativity is shown to be assocd. with enhanced dipole moments of the peptide backbone upon helix formation. These results indicate the polarizable force field to more accurately model peptide-folding cooperativity based on its phys. realistic treatment of electronic polarizability.
- 31Shi, Y.; Xia, Z.; Zhang, J.; Best, R.; Wu, C.; Ponder, J. W.; Ren, P. Polarizable Atomic Multipole-Based AMOEBA Force Field for Proteins J. Chem. Theory Comput. 2013, 9 (9) 4046– 4063 DOI: 10.1021/ct400370231https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFKrsrjN&md5=df5d457e466f177cc83c46ab7ff5c506Polarizable Atomic Multipole-Based AMOEBA Force Field for ProteinsShi, Yue; Xia, Zhen; Zhang, Jiajing; Best, Robert; Wu, Chuanjie; Ponder, Jay W.; Ren, PengyuJournal of Chemical Theory and Computation (2013), 9 (9), 4046-4063CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)Development of the AMOEBA (at. multipole optimized energetics for biomol. simulation) force field for proteins is presented. The current version (AMOEBA-2013) utilizes permanent electrostatic multipole moments through the quadrupole at each atom, and explicitly treats polarization effects in various chem. and phys. environments. The at. multipole electrostatic parameters for each amino acid residue type are derived from high-level gas phase quantum mech. calcns. via a consistent and extensible protocol. Mol. polarizability is modeled via a Thole-style damped interactive induction model based upon distributed at. polarizabilities. Inter- and intramol. polarization is treated in a consistent fashion via the Thole model. The intramol. polarization model ensures transferability of electrostatic parameters among different conformations, as demonstrated by the agreement between QM and AMOEBA electrostatic potentials, and dipole moments of dipeptides. The backbone and side chain torsional parameters were detd. by comparing to gas-phase QM (RI-TRIM MP2/CBS) conformational energies of dipeptides and to statistical distributions from the Protein Data Bank. Mol. dynamics simulations are reported for short peptides in explicit water to examine their conformational properties in soln. Overall the calcd. conformational free energies and J-coupling consts. are consistent with PDB statistics and exptl. NMR results, resp. In addn., the exptl. crystal structures of a no. of proteins are well maintained during mol. dynamics (MD) simulation. While further calcns. are necessary to fully validate the force field, initial results suggest the AMOEBA polarizable multipole force field is able to describe the structure and energetics of peptides and proteins, in both gas-phase and soln. environments.
- 32Laury, M. L.; Wang, L.-P.; Pande, V. S.; Head-Gordon, T. L.; Ponder, J. W. Revised Parameters for the AMOEBA Polarizable Atomic Multipole Water Model J. Phys. Chem. B 2015, 119 (29) 9423– 9437 DOI: 10.1021/jp510896n32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXislSmsL8%253D&md5=254aba3db5c0fbf6f70f4b8036048acbRevised Parameters for the AMOEBA Polarizable Atomic Multipole Water ModelLaury, Marie L.; Wang, Lee-Ping; Pande, Vijay S.; Head-Gordon, Teresa; Ponder, Jay W.Journal of Physical Chemistry B (2015), 119 (29), 9423-9437CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)A set of improved parameters for the AMOEBA polarizable at. multipole water model is developed. An automated procedure, ForceBalance, is used to adjust model parameters to enforce agreement with ab initio-derived results for water clusters and exptl. data for a variety of liq. phase properties across a broad temp. range. The values reported here for the new AMOEBA14 water model represent a substantial improvement over the previous AMOEBA03 model. The AMOEBA14 model accurately predicts the temp. of max. d. and qual. matches the exptl. d. curve across temps. from 249 to 373 K. Excellent agreement is obsd. for the AMOEBA14 model in comparison to exptl. properties as a function of temp., including the second virial coeff., enthalpy of vaporization, isothermal compressibility, thermal expansion coeff., and dielec. const. The viscosity, self-diffusion const., and surface tension are also well reproduced. In comparison to high-level ab initio results for clusters of 2-20 water mols., the AMOEBA14 model yields results similar to AMOEBA03 and the direct polarization iAMOEBA models. With advances in computing power, calibration data, and optimization techniques, we recommend the use of the AMOEBA14 water model for future studies employing a polarizable water model.
- 33Wang, Q.; Rackers, J. A.; He, C.; Qi, R.; Narth, C.; Lagardère, L.; Gresh, N.; Ponder, J. W.; Piquemal, J.-P.; Ren, P. A General Model for Treating Short-Range Electrostatic Penetration in a Molecular Mechanics Force Field J. Chem. Theory Comput. 2015, 11 (6) 2609– 2618 DOI: 10.1021/acs.jctc.5b0026733https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXntlCntrw%253D&md5=0ccb1ad26499eccc00a0a7ea0653af67General Model for Treating Short-Range Electrostatic Penetration in a Molecular Mechanics Force FieldWang, Qiantao; Rackers, Joshua A.; He, Chenfeng; Qi, Rui; Narth, Christophe; Lagardere, Louis; Gresh, Nohad; Ponder, Jay W.; Piquemal, Jean-Philip; Ren, PengyuJournal of Chemical Theory and Computation (2015), 11 (6), 2609-2618CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)Classical mol. mechanics force fields typically model interat. electrostatic interactions with point charges or multipole expansions, which can fail for atoms in close contact due to the lack of a description of penetration effects between their electron clouds. These short-range penetration effects can be significant and are essential for accurate modeling of intermol. interactions. In this work we report parametrization of an empirical charge-charge function previously reported to correct for the missing penetration term in std. mol. mechanics force fields. For this purpose, we have developed a database (S101×7) of 101 unique mol. dimers, each at 7 different intermol. distances. Electrostatic, induction/polarization, repulsion, and dispersion energies, as well as the total interaction energy for each complex in the database are calcd. using the SAPT2 + method. This empirical penetration model significantly improves agreement between point multipole and quantum mech. electrostatic energies across the set of dimers and distances, while using only a limited set of parameters for each chem. element. Given the simplicity and effectiveness of the model, we expect the electrostatic penetration correction will become a std. component of future mol. mechanics force fields.
- 34Lagardère, L.; Lipparini, F.; Polack, E.; Stamm, B.; Schnieders, M.; Cances, E.; Ren, P.; Maday, Y.; Piquemal, J.-P. Scalable Evaluation of Polarization Energy and Associated Forces in Polarizable Molecular Dynamics: II.Towards Massively Parallel Computations Using Smooth Particle Mesh Ewald J. Chem. Theory Comput. 2015, 11 (6) 2589– 2599 DOI: 10.1021/acs.jctc.5b0017134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXnvFClsbo%253D&md5=c0657f8139af4f0e84812b3bb7490059Scalable Evaluation of Polarization Energy and Associated Forces in Polarizable Molecular Dynamics: II. Toward Massively Parallel Computations Using Smooth Particle Mesh EwaldLagardere, Louis; Lipparini, Filippo; Polack, Etienne; Stamm, Benjamin; Cances, Eric; Schnieders, Michael; Ren, Pengyu; Maday, Yvon; Piquemal, Jean-PhilipJournal of Chemical Theory and Computation (2015), 11 (6), 2589-2599CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)The authors present a parallel implementation of point dipole-based polarizable force fields for mol. dynamics (MD) simulations with periodic boundary conditions (PBC). The smooth particle mesh Ewald technique is combined with two optimal iterative strategies, namely, a preconditioned conjugate gradient solver and a Jacobi solver in conjunction with the direct inversion in the iterative subspace for convergence acceleration, to solve the polarization equations. Both solvers exhibit very good parallel performances and overall very competitive timings in an energy and force computation needed to perform a MD step. Various tests on large systems are provided in the context of the polarizable AMOEBA force field as implemented in the newly developed Tinker-HP package, which is the 1st implementation of a polarizable model that makes large-scale expts. for massively parallel PBC point dipole models possible. Using a large no. of cores offers a significant acceleration of the overall process involving the iterative methods within the context of SPME and a noticeable improvement of the memory management, giving access to very large systems (hundreds of thousands of atoms) as the algorithm naturally distributes the data on different cores. Coupled with advanced MD techniques, gains ranging from 2 to 3 orders of magnitude in time are now possible compared to nonoptimized, sequential implementations, giving new directions for polarizable mol. dynamics with periodic boundary conditions using massively parallel implementations.
- 35Albaugh, A.; Demerdash, O.; Head-Gordon, T. An Efficient and Stable Hybrid Extended Lagrangian/self-Consistent Field Scheme for Solving Classical Mutual Induction J. Chem. Phys. 2015, 143 (17) 174104 DOI: 10.1063/1.4933375There is no corresponding record for this reference.
- 36Lindert, S.; Bucher, D.; Eastman, P.; Pande, V.; McCammon, J. A. Accelerated Molecular Dynamics Simulations with the AMOEBA Polarizable Force Field on Graphics Processing Units J. Chem. Theory Comput. 2013, 9 (11) 4684– 4691 DOI: 10.1021/ct400514p36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1WltbvK&md5=db44fd3f64a298b6870a50a850aef72aAccelerated Molecular Dynamics Simulations with the AMOEBA Polarizable Force Field on Graphics Processing UnitsLindert, Steffen; Bucher, Denis; Eastman, Peter; Pande, Vijay; McCammon, J. AndrewJournal of Chemical Theory and Computation (2013), 9 (11), 4684-4691CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)The accelerated mol. dynamics (aMD) method has recently been shown to enhance the sampling of biomols. in mol. dynamics (MD) simulations, often by several orders of magnitude. Here, the authors describe an implementation of the aMD method for the OpenMM application layer that takes full advantage of graphics processing units (GPUs) computing. The aMD method is shown to work in combination with the AMOEBA polarizable force field (AMOEBA-aMD), allowing the simulation of long time-scale events with a polarizable force field. Benchmarks are provided to show that the AMOEBA-aMD method is efficiently implemented and produces accurate results in its std. parametrization. For the BPTI protein, the protein structure described with AMOEBA remains stable even on the extended time scales accessed at high levels of accelerations. For the DNA repair metalloenzyme endonuclease IV, the use of the AMOEBA force field is a significant improvement over fixed charged models for describing the enzyme active-site. The new AMOEBA-aMD method is publicly available (http://wiki.simtk.org/openmm/VirtualRepository) and promises to be interesting for studying complex systems that can benefit from both the use of a polarizable force field and enhanced sampling.
- 37Peng, X.; Zhang, Y.; Chu, H.; Li, G. Free Energy Simulations with the AMOEBA Polarizable Force Field and Metadynamics on GPU Platform J. Comput. Chem. 2016, 37 (6) 614– 622 DOI: 10.1002/jcc.24227There is no corresponding record for this reference.
- 38Wu, J. C.; Chattree, G.; Ren, P. Automation of AMOEBA Polarizable Force Field Parameterization for Small Molecules Theor. Chem. Acc. 2012, 131 (3) 1138 DOI: 10.1007/s00214-012-1138-638https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2srms1OntA%253D%253D&md5=5432a389f20925526b9b0c25c9646ef0Automation of AMOEBA polarizable force field parameterization for small moleculesWu Johnny C; Chattree Gaurav; Ren PengyuTheoretical chemistry accounts (2012), 131 (3), 1138 ISSN:1432-881X.A protocol to generate parameters for the AMOEBA polarizable force field for small organic molecules has been established, and polarizable atomic typing utility, Poltype, which fully automates this process, has been implemented. For validation, we have compared with quantum mechanical calculations of molecular dipole moments, optimized geometry, electrostatic potential, and conformational energy for a variety of neutral and charged organic molecules, as well as dimer interaction energies of a set of amino acid side chain model compounds. Furthermore, parameters obtained in gas phase are substantiated in liquid-phase simulations. The hydration free energy (HFE) of neutral and charged molecules have been calculated and compared with experimental values. The RMS error for the HFE of neutral molecules is less than 1 kcal/mol. Meanwhile, the relative error in the predicted HFE of salts (cations and anions) is less than 3% with a correlation coefficient of 0.95. Overall, the performance of Poltype is satisfactory and provides a convenient utility for applications such as drug discovery. Further improvement can be achieved by the systematic study of various organic compounds, particularly ionic molecules, and refinement and expansion of the parameter database.
- 39Manzoni, F.; Söderhjelm, P. Prediction of Hydration Free Energies for the SAMPL4 Data Set with the AMOEBA Polarizable Force Field J. Comput.-Aided Mol. Des. 2014, 28 (3) 235– 244 DOI: 10.1007/s10822-014-9733-3There is no corresponding record for this reference.
- 40Muddana, H. S.; Fenley, A. T.; Mobley, D. L.; Gilson, M. K. The SAMPL4 Host–guest Blind Prediction Challenge: An Overview J. Comput.-Aided Mol. Des. 2014, 28 (4) 305– 317 DOI: 10.1007/s10822-014-9735-140https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjs1Ggs74%253D&md5=04ade7377b0bee4428baba44db3d2a83The SAMPL4 host-guest blind prediction challenge: an overviewMuddana, Hari S.; Fenley, Andrew T.; Mobley, David L.; Gilson, Michael K.Journal of Computer-Aided Molecular Design (2014), 28 (4), 305-317CODEN: JCADEQ; ISSN:0920-654X. (Springer)A review. Prospective validation of methods for computing binding affinities can help assess their predictive power and thus set reasonable expectations for their performance in drug design applications. Supramol. host-guest systems are excellent model systems for testing such affinity prediction methods, because their small size and limited conformational flexibility, relative to proteins, allows higher throughput and better numerical convergence. The SAMPL4 prediction challenge therefore included a series of host-guest systems, based on two hosts, cucurbit[7]uril and octa-acid. Binding affinities in aq. soln. were measured exptl. for a total of 23 guest mols. Participants submitted 35 sets of computational predictions for these host-guest systems, based on methods ranging from simple docking, to extensive free energy simulations, to quantum mech. calcns. Over half of the predictions provided better correlations with expt. than two simple null models, but most methods underperformed the null models in terms of root mean squared error and linear regression slope. Interestingly, the overall performance across all SAMPL4 submissions was similar to that for the prior SAMPL3 host-guest challenge, although the experimentalists took steps to simplify the current challenge. While some methods performed fairly consistently across both hosts, no single approach emerged as consistent top performer, and the nonsystematic nature of the various submissions made it impossible to draw definitive conclusions regarding the best choices of energy models or sampling algorithms. Salt effects emerged as an issue in the calcn. of abs. binding affinities of cucurbit[7]uril-guest systems, but were not expected to affect the relative affinities significantly. Useful directions for future rounds of the challenge might involve encouraging participants to carry out some calcns. that replicate each others' studies, and to systematically explore parameter options.
- 41Ren, P. Y.; Ponder, J. W. Consistent Treatment of Inter- and Intramolecular Polarization in Molecular Mechanics Calculations J. Comput. Chem. 2002, 23 (16) 1497– 1506 DOI: 10.1002/jcc.1012741https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XosF2rtr4%253D&md5=4f43548e95124d23ba655451cd332232Consistent treatment of inter- and intramolecular polarization in molecular mechanics calculationsRen, Pengyu; Ponder, Jay W.Journal of Computational Chemistry (2002), 23 (16), 1497-1506CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)A protocol is described for the treatment of mol. polarization in force field calcns. The resulting model is consistent in that both inter- and intramol. polarization are handled within a single scheme. An anal. formula for removing intramol. polarization from a set of at. multipoles for an arbitrary static structure or conformation is given. With the help of the intramol. polarization, these permanent at. multipoles can then be applied in modeling alternative conformations of a mol. Equipped with this simple technique, one can derive transferable electrostatic parameters for peptides and proteins using flexible model compds. such as dipeptides. The proposed procedure is tested for its ability to describe the electrostatic potential around various configurations of the N-methylacetamide dimer. The effect of different intramol. polarization schemes on the accuracy of a force field model of the electrostatic potential of alanine dipeptide is investigated. A group-based scheme for including direct intramol. polarization is shown to be most successful in accounting for the conformational dependence of electrostatic potentials.
- 42Ren, P. Y.; Ponder, J. W. Polarizable Atomic Multipole Water Model for Molecular Mechanics Simulation J. Phys. Chem. B 2003, 107 (24) 5933– 5947 DOI: 10.1021/jp027815+42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjvFOhsro%253D&md5=f9cc56cc91cc9c86df686004dd9f8ff5Polarizable Atomic Multipole Water Model for Molecular Mechanics SimulationRen, Pengyu; Ponder, Jay W.Journal of Physical Chemistry B (2003), 107 (24), 5933-5947CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)A new classical empirical potential is proposed for water. The model uses a polarizable at. multipole description of electrostatic interactions. Multipoles through the quadrupole are assigned to each at. center based on a distributed multipole anal. (DMA) derived from large basis set MO calcns. on the water monomer. Polarization is treated via self-consistent induced at. dipoles. A modified version of Thole's interaction model is used to damp induction at short range. Repulsion-dispersion (vdW) effects are computed from a buffered 14-7 potential. In a departure from most current water potentials, we find that significant vdW parameters are necessary on hydrogen as well as oxygen. The new potential is fully flexible and has been tested vs. a variety of exptl. data and quantum calcns. for small clusters, liq. water, and ice. Overall, excellent agreement with exptl. and high level ab initio results is obtained for numerous properties, including cluster structures and energetics and bulk thermodn. and structural measures. The parametrization scheme described here is easily extended to other mol. systems, and the resulting water potential should provide a useful explicit solvent model for org. solutes and biopolymer modeling.
- 43Thole, B. T. Molecular Polarizabilities Calculated with a Modified Dipole Interaction Chem. Phys. 1981, 59 (3) 341– 350 DOI: 10.1016/0301-0104(81)85176-243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3MXltl2jurk%253D&md5=a92d26bef31ef7e26a244c3f15d5b8a6Molecular polarizabilities calculated with a modified dipole interactionThole, B. T.Chemical Physics (1981), 59 (3), 341-50CODEN: CMPHC2; ISSN:0301-0104.The point dipole interaction model for mol. polarizability recently proposed by J. Applequist, et al., (1972) is modified by replacing the point dipole interaction by an interaction between smeared out dipoles. Rules are developed to indicate plausible forms for this modified interaction. The polarizabilities of a wide range of chem. different mols. can be calcd., using for each atom one polarizability independent of its chem. environment. The errors are comparable to exptl. uncertainty. Special care is taken to produce a model that tends to avoid infinite polarizabilities without use of cutoffs at short distances.
- 44Jakalian, A.; Jack, D. B.; Bayly, C. I. Fast, Efficient Generation of High-Quality Atomic Charges. AM1-BCC Model: II. Parameterization and Validation J. Comput. Chem. 2002, 23 (16) 1623– 1641 DOI: 10.1002/jcc.1012844https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XosF2rt74%253D&md5=3f2b738617bb17b2898f7ac4d751d7ecFast, efficient generation of high-quality atomic charges. AM1-BCC model: II. parameterization and validationJakalian, Araz; Jack, David B.; Bayly, Christopher I.Journal of Computational Chemistry (2002), 23 (16), 1623-1641CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)We present the first global parameterization and validation of a novel charge model, called AM1-BCC, which quickly and efficiently generates high-quality at. charges for computer simulations of org. mols. in polar media. The goal of the charge model is to produce at. charges that emulate the HF/6-31G* electrostatic potential (ESP) of a mol. Underlying electronic structure features, including formal charge and electron delocalization, are first captured by AM1 population charges; simple additive bond charge corrections (BCCs) are then applied to these AM1 at. charges to produce the AM1-BCC charges. The parameterization of BCCs was carried out by fitting to the HF/6-31G* ESP of a training set of >2700 mols. Most org. functional groups and their combinations were sampled, as well as an extensive variety of cyclic and fused bicyclic heteroaryl systems. The resulting BCC parameters allow the AM1-BCC charging scheme to handle virtually all types of org. compds. listed in The Merck Index and the NCI Database. Validation of the model was done through comparisons of hydrogen-bonded dimer energies and relative free energies of solvation using AM1-BCC charges in conjunction with the 1994 Cornell et al. forcefield for AMBER. Homo-dimer and hetero-dimer hydrogen-bond energies of a diverse set of org. mols. were reproduced to within 0.95 kcal/mol RMS deviation from the ab initio values, and for DNA dimers the energies were within 0.9 kcal/mol RMS deviation from ab initio values. The calcd. relative free energies of solvation for a diverse set of monofunctional isosteres were reproduced to within 0.69 kcal/mol of expt. In all these validation tests, AMBER with the AM1-BCC charge model maintained a correlation coeff. above 0.96. Thus, the parameters presented here for use with the AM1-BCC method present a fast, accurate, and robust alternative to HF/6-31G* ESP-fit charges for general use with the AMBER force field in computer simulations involving org. small mols.
- 45Bayly, C. I.; Cieplak, P.; Cornell, W. D.; Kollman, P. A. A Well-Behaved Electrostatic Potential Based Method Using Charge Restraints for Deriving Atomic Charges: The RESP Model J. Phys. Chem. 1993, 97, 10269– 10280 DOI: 10.1021/j100142a00445https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXlvVyqsLs%253D&md5=e65c6a556ffc174df4f327687912a0bdA well-behaved electrostatic potential based method using charge restraints for deriving atomic charges: the RESP modelBayly, Christopher I.; Cieplak, Piotr; Cornell, Wendy; Kollman, Peter A.Journal of Physical Chemistry (1993), 97 (40), 10269-80CODEN: JPCHAX; ISSN:0022-3654.The authors present a new approach to generating electrostatic potential (ESP) derived charges for mols. The major strength of electrostatic potential derived charges is that they optimally reproduce the intermol. interaction properties of mols. with a simple two-body additive potential, provided, of course, that a suitably accurate level of quantum mech. calcn. is used to derive the ESP around the mol. Previously, the major weaknesses of these charges have been that they were not easily transferably between common functional groups in related mols., they have often been conformationally dependent, and the large charges that frequently occur can be problematic for simulating intramol. interactions. Introducing restraints in the form of a penalty function into the fitting process considerably reduces the above problems, with only a minor decrease in the quality of the fit to the quantum mech. ESP. Several other refinements in addn. to the restrained electrostatic potential (RESP) fit yield a general and algorithmic charge fitting procedure for generating atom-centered point charges. This approach can thus be recommended for general use in mol. mechanics, mol. dynamics, and free energy calcns. for any org. or bioorg. system.
- 46Wang, J.; Wolf, R. M.; Caldwell, J. W.; Kollman, P. A.; Case, D. A. Development and Testing of a General Amber Force Field J. Comput. Chem. 2004, 25 (9) 1157– 1174 DOI: 10.1002/jcc.2003546https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXksFakurc%253D&md5=2992017a8cf51f89290ae2562403b115Development and testing of a general Amber force fieldWang, Junmei; Wolf, Romain M.; Caldwell, James W.; Kollman, Peter A.; Case, David A.Journal of Computational Chemistry (2004), 25 (9), 1157-1174CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)We describe here a general Amber force field (GAFF) for org. mols. GAFF is designed to be compatible with existing Amber force fields for proteins and nucleic acids, and has parameters for most org. and pharmaceutical mols. that are composed of H, C, N, O, S, P, and halogens. It uses a simple functional form and a limited no. of atom types, but incorporates both empirical and heuristic models to est. force consts. and partial at. charges. The performance of GAFF in test cases is encouraging. In test I, 74 crystallog. structures were compared to GAFF minimized structures, with a root-mean-square displacement of 0.26 Å, which is comparable to that of the Tripos 5.2 force field (0.25 Å) and better than those of MMFF 94 and CHARMm (0.47 and 0.44 Å, resp.). In test II, gas phase minimizations were performed on 22 nucleic acid base pairs, and the minimized structures and intermol. energies were compared to MP2/6-31G* results. The RMS of displacements and relative energies were 0.25 Å and 1.2 kcal/mol, resp. These data are comparable to results from Parm99/RESP (0.16 Å and 1.18 kcal/mol, resp.), which were parameterized to these base pairs. Test III looked at the relative energies of 71 conformational pairs that were used in development of the Parm99 force field. The RMS error in relative energies (compared to expt.) is about 0.5 kcal/mol. GAFF can be applied to wide range of mols. in an automatic fashion, making it suitable for rational drug design and database searching.
- 47Wang, J.; Wang, W.; Kollman, P. A.; Case, D. A. Automatic Atom Type and Bond Type Perception in Molecular Mechanical Calculations J. Mol. Graphics Modell. 2006, 25 (2) 247– 260 DOI: 10.1016/j.jmgm.2005.12.00547https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xps1Gis7g%253D&md5=8031a21d2784d5dea12e70868522aa61Automatic atom type and bond type perception in molecular mechanical calculationsWang, Junmei; Wang, Wei; Kollman, Peter A.; Case, David A.Journal of Molecular Graphics & Modelling (2006), 25 (2), 247-260CODEN: JMGMFI; ISSN:1093-3263. (Elsevier Inc.)In mol. mechanics (MM) studies, atom types and/or bond types of mols. are needed to det. prior to energy calcns. The authors present here an automatic algorithm of perceiving atom types that are defined in a description table, and an automatic algorithm of assigning bond types just based on at. connectivity. The algorithms have been implemented in a new module of the AMBER packages. This auxiliary module, antechamber (roughly meaning "before AMBER"), can be applied to generate necessary inputs of leap-the AMBER program to generate topologies for minimization, mol. dynamics, etc., for most org. mols. The algorithms behind the manipulations may be useful for other mol. mech. packages as well as applications that need to designate atom types and bond types.
- 48Stone, A. J. Distributed Multipole Analysis, or How to Describe a Molecular Charge Distribution Chem. Phys. Lett. 1981, 83 (2) 233– 239 DOI: 10.1016/0009-2614(81)85452-848https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3MXmt1yitbY%253D&md5=1a7ac695fa444006688ea669d36a3d55Distributed multipole analysis, or how to describe a molecular charge distributionStone, A. J.Chemical Physics Letters (1981), 83 (2), 233-9CODEN: CHPLBC; ISSN:0009-2614.A method of analyzing mol. wavefunctions is described. It can be regarded as an extension of Mulliken population anal., and can be used both to give a qual. or quant. picture of the mol. charge distribution, and in the accurate evaluation of mol. multipole moments of arbitrary order with negligible computational effort.
- 49Stone, A. J.; Alderton, M. Distributed Multipole Analysis: Methods and Applications Mol. Phys. 1985, 56 (5) 1047– 1064 DOI: 10.1080/00268978500102891There is no corresponding record for this reference.
- 50Shi, Y.; Wu, C. J.; Ponder, J. W.; Ren, P. Y. Multipole Electrostatics in Hydration Free Energy Calculations J. Comput. Chem. 2011, 32 (5) 967– 977 DOI: 10.1002/jcc.2168150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXitleju7s%253D&md5=364014fda294cf4cfcb72253a38df389Multipole electrostatics in hydration free energy calculationsShi, Yue; Wu, Chuan-Jie; Ponder, Jay W.; Ren, Peng-YuJournal of Computational Chemistry (2011), 32 (5), 967-977CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)Hydration free energy (HFE) is generally used for evaluating mol. soly., which is an important property for pharmaceutical and chem. engineering processes. Accurately predicting HFE is also recognized as one fundamental capability of mol. mechanics force field. Here, the authors present a systematic investigation on HFE calcns. with AMOEBA polarizable force field at various parameterization and simulation conditions. The HFEs of seven small org. mols. have been obtained alchem. using the Bennett Acceptance Ratio method. The authors have compared two approaches to derive the at. multipoles from quantum mech. calcns.: one directly from the new distributed multipole anal. and the other involving fitting to the electrostatic potential around the mols. Wave functions solved at the MP2 level with four basis sets (6-311G*, 6-311++G(2d,2p), cc-pVTZ, and aug-cc-pVTZ) are used to derive the at. multipoles. HFEs from all four basis sets show a reasonable agreement with exptl. data (root mean square error 0.63 kcal/mol for aug-cc-pVTZ). The aug-cc-pVTZ gives the best performance when used with AMOEBA, and 6-311++G(2d,2p) is comparable but more efficient for larger systems. The results suggest that the inclusion of diffuse basis functions is important for capturing intermol. interactions. The effect of long-range correction to van der Waals interaction on the hydration free energies is about 0.1 kcal/mol when the cutoff is 12Å, and increases linearly with the no. of atoms in the solute/ligand. In addn., the authors also discuss the results from a hybrid approach that combines polarizable solute with fixed-charge water in the HFE calcn.
- 51Ren, P. Y.; Ponder, J. W. Temperature and Pressure Dependence of the AMOEBA Water Model J. Phys. Chem. B 2004, 108 (35) 13427– 13437 DOI: 10.1021/jp048433251https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmt12ktbs%253D&md5=e8c36c8fb511134c7e861b6b11cd999aTemperature and Pressure Dependence of the AMOEBA Water ModelRen, Pengyu; Ponder, Jay W.Journal of Physical Chemistry B (2004), 108 (35), 13427-13437CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)The temp. and pressure dependence of the previously developed polarizable at.-multipole-based AMOEBA water potential is explored. The energetic, structural, and dynamical properties of liq. water are investigated via mol. dynamics simulations at various temps. ranging from 248 K to 360 K and pressures up to 5000 atm. The AMOEBA model, derived solely from known gas-phase and room-temp. liq. properties, produces a max. liq. d. around 290 K at 1 atm. The quant. agreement between AMOEBA and expt. is good in general for d., heat of vaporization, radial distribution functions, magnetic shielding, self-diffusion, and static dielec. const. Based on comparison of two variants of AMOEBA water, as well as results from other water potentials, it is suggested that the temp. at which the max. d. occurs is closely related to the tetrahedral hydrogen-bonding network in the bulk. Explicit dipole polarization and internal geometry in the liq. play vital roles in detg. the self-diffusion and dielec. consts. The development of the AMOEBA model demonstrates that a realistic and well-balanced at. potential requires a sophisticated electrostatic description and inclusion of many-body polarization. Within the current polarizable at. multipole framework, a potential derived from limited gas phase and condensed phase properties can be applied across a range of phys. and thermodn. environments.
- 52Ponder, J. TINKER: Software Tools for Molecular Design; Washington University School of Medicine: St. Louis, MO, 2001.There is no corresponding record for this reference.
- 53Case, D. A.; Babin, V.; Berryman, J. T.; Betz, R. M.; Cai, Q.; Cerutti, D. S.; Cheatham, T. E. I.; Darden, T. A.; Duke, R. E.; Gohlke, H.; Goetz, A. W.; Gusarov, S.; Homeyer, N.; Janowski, P. A.; Kaus, J.; Kolossváry, I.; Kovalenko, A.; Lee, T. S.; LeGrand, S.; Luchko, T.; Luo, R.; Madej, B.; Merz, K. M., Jr.; Paesani, F.; Roe, D. R.; Roitberg, A. E.; Sagui, C.; Salomon-Ferrer, R.; Seabra, G.; Simmerling, C. L.; Smith, W.; Swails, J. M.; Walker, R. C.; Wang, J.; Wolf, R. M.; Wu, X.; Kollman, P. A. AMBER 14; University of California: San Francisco, CA, 2014.There is no corresponding record for this reference.
- 54Pastor, R. W.; Brooks, B. R.; Szabo, A. An Analysis of the Accuracy of Langevin and Molecular Dynamics Algorithms Mol. Phys. 1988, 65, 1409– 1419 DOI: 10.1080/00268978800101881There is no corresponding record for this reference.
- 55Loncharich, R. J.; Brooks, B. R.; Pastor, R. W. Langevin Dynamics of Peptides: The Frictional Dependence of Isomerization Rates of N-Acetylalanyl-N′-methylamide Biopolymers 1992, 32 (5) 523– 535 DOI: 10.1002/bip.36032050855https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XisFGqu7o%253D&md5=9209a0b3485915887d1b03fefcbadc35Langevin dynamics of peptides: the frictional dependence of isomerization rates of N-acetylalanyl-N'-methylamideLoncharich, Richard J.; Brooks, Bernard R.; Pastor, Richard W.Biopolymers (1992), 32 (5), 523-35CODEN: BIPMAA; ISSN:0006-3525.The rate const. for the transition between the equatorial and axial conformations of N-acetylalanyl-N'-methylamide has been detd. from Langevin dynamics (LD) simulations with no explicit solvent. The isomerization rate is max. at collision frequency γ = 2 ps-1, shows diffusive character for γ ≥ 10 ps-1, but does not approach zero even at γ = 0.01 ps-1. This behavior differs from that found for a one-dimensional bistable potential and indicates that both collisional energy transfer with solvent and vibrational energy transfer between internal modes are important in the dynamics of barrier crossing for this system. It is suggested that conformational searches of peptides be carried out using LD with a collision frequency that maximizes the isomerization rate (i.e., γ ≈ 2 ps-1). This method is expected to be more efficient than either mol. dynamics in vacuo (which corresponds to LD with γ = 0) or mol. dynamics in solvent (where dynamics is largely diffusive).
- 56Izaguirre, J. A.; Catarello, D. P.; Wozniak, J. M.; Skeel, R. D. Langevin Stabilization of Molecular Dynamics J. Chem. Phys. 2001, 114, 2090– 2098 DOI: 10.1063/1.133299656https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXms1eltQ%253D%253D&md5=6f5c141b113cc7a8cacea7e15f9fb007Langevin stabilization of molecular dynamicsIzaguirre, Jesus A.; Catarello, Daniel P.; Wozniak, Justin M.; Skeel, Robert D.Journal of Chemical Physics (2001), 114 (5), 2090-2098CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)In this paper we show the possibility of using very mild stochastic damping to stabilize long time step integrators for Newtonian mol. dynamics. More specifically, stable and accurate integrations are obtained for damping coeffs. that are only a few percent of the natural decay rate of processes of interest, such as the velocity autocorrelation function. Two new multiple time stepping integrators, Langevin Molly (LM) and Brunger-Brooks-Karplus-Molly (BBK-M), are introduced in this paper. Both use the mollified impulse method for the Newtonian term. LM uses a discretization of the Langevin equation that is exact for the const. force, and BBK-M uses the popular Brunger-Brooks-Karplus integrator (BBK). These integrators, along with an extrapolative method called LN, are evaluated across a wide range of damping coeff. values. When large damping coeffs. are used, as one would for the implicit modeling of solvent mols., the method LN is superior, with LM closely following. However, with mild damping of 0.2 ps-1, LM produces the best results, allowing long time steps of 14 fs in simulations contg. explicitly modeled flexible water. With BBK-M and the same damping coeff., time steps of 12 fs are possible for the same system. Similar results are obtained for a solvated protein-DNA simulation of estrogen receptor ER with estrogen response element ERE. A parallel version of BBK-M runs nearly three times faster than the Verlet-I/r-RESPA (reversible ref. system propagator algorithm) when using the largest stable time step on each one, and it also parallelizes well. The computation of diffusion coeffs. for flexible water and ER/ERE shows that when mild damping of up to 0.2 ps-1 is used the dynamics are not significantly distorted.
- 57Berendsen, H. J. C.; Postma, J. P. M.; van Gunsteren, W. F.; DiNola, A.; Haak, J. R. Molecular Dynamics with Coupling to an External Bath J. Chem. Phys. 1984, 81 (8) 3684 DOI: 10.1063/1.44811857https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2cXmtlGksbY%253D&md5=5510dc00297d63b91ee3a7a4ae5aacb1Molecular dynamics with coupling to an external bathBerendsen, H. J. C.; Postma, J. P. M.; Van Gunsteren, W. F.; DiNola, A.; Haak, J. R.Journal of Chemical Physics (1984), 81 (8), 3684-90CODEN: JCPSA6; ISSN:0021-9606.In mol. dynamics (MD) simulations, the need often arises to maintain such parameters as temp. or pressure rather than energy and vol., or to impose gradients for studying transport properties in nonequil. MD. A method is described to realize coupling to an external bath with const. temp. or pressure with adjustable time consts. for the coupling. The method is easily extendable to other variables and to gradients, and can be applied also to polyat. mols. involving internal constraints. The influence of coupling time consts. on dynamical variables is evaluated. A leap-frog algorithm is presented for the general case involving constraints with coupling to both a const. temp. and a const. pressure bath.
- 58Sagui, C.; Pedersen, L. G.; Darden, T. A. Towards an Accurate Representation of Electrostatics in Classical Force Fields: Efficient Implementation of Multipolar Interactions in Biomolecular Simulations J. Chem. Phys. 2004, 120 (1) 73– 87 DOI: 10.1063/1.163079158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXotVw%253D&md5=b9cf8b78c1d35fd103a5b2147c27b471Towards an accurate representation of electrostatics in classical force fields: Efficient implementation of multipolar interactions in biomolecular simulationsSagui, Celeste; Pedersen, Lee G.; Darden, Thomas A.Journal of Chemical Physics (2004), 120 (1), 73-87CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)The accurate simulation of biol. active macromols. faces serious limitations that originate in the treatment of electrostatics in the empirical force fields. The current use of "partial charges" is a significant source of errors, since these vary widely with different conformations. By contrast, the mol. electrostatic potential (MEP) obtained through the use of a distributed multipole moment description, has been shown to converge to the quantum MEP outside the van der Waals surface, when higher order multipoles are used. However, in spite of the considerable improvement to the representation of the electronic cloud, higher order multipoles are not part of current classical biomol. force fields due to the excessive computational cost. In this paper we present an efficient formalism for the treatment of higher order multipoles in Cartesian tensor formalism. The Ewald "direct sum" is evaluated through a McMurchie-Davidson formalism [L. McMurchie and E. Davidson, J. Comput. Phys. 26, 218 (1978)]. The "reciprocal sum" has been implemented in three different ways: using an Ewald scheme, a particle mesh Ewald (PME) method, and a multigrid-based approach. We find that even though the use of the McMurchie-Davidson formalism considerably reduces the cost of the calcn. with respect to the std. matrix implementation of multipole interactions, the calcn. in direct space remains expensive. When most of the calcn. is moved to reciprocal space via the PME method, the cost of a calcn. where all multipolar interactions (up to hexadecapole-hexadecapole) are included is only about 8.5 times more expensive than a regular AMBER 7 [D. A. Pearlman et al., Comput. Phys. Commun. 91, 1 (1995)] implementation with only charge-charge interactions. The multigrid implementation is slower but shows very promising results for parallelization. It provides a natural way to interface with continuous, Gaussian-based electrostatics in the future. It is hoped that this new formalism will facilitate the systematic implementation of higher order multipoles in classical biomol. force fields.
- 59Cerutti, D. S.; Duke, R.; Freddolino, P. L.; Fan, H.; Lybrand, T. P. A Vulnerability in Popular Molecular Dynamics Packages Concerning Langevin and Andersen Dynamics J. Chem. Theory Comput. 2008, 4 (10) 1669– 1680 DOI: 10.1021/ct800217359https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtV2lurfO&md5=d6cb4ac701c7c0268114a54030cad05fA Vulnerability in Popular Molecular Dynamics Packages Concerning Langevin and Andersen DynamicsCerutti, David S.; Duke, Robert; Freddolino, Peter L.; Fan, Hao; Lybrand, Terry P.Journal of Chemical Theory and Computation (2008), 4 (10), 1669-1680CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)We report a serious problem assocd. with a no. of current implementations of Andersen and Langevin dynamics algorithms. When long simulations are run in many segments, it is sometimes possible to have a repeating sequence of pseudorandom nos. enter the calcn. The authors show that, if the sequence repeats rapidly, the resulting artifacts can quickly denature biomols. and are then easily detectable. However, if the sequence repeats less frequently, the artifacts become subtle and easily overlooked. The authors derive a formula for the underlying cause of artifacts in the case of the Langevin thermostat, and find it vanishes slowly as the inverse square root of the no. of time steps per simulation segment. Numerous examples of simulation artifacts are presented, including dissocn. of a tetrameric protein after 110 ns of dynamics, redns. in at. fluctuations for a small protein in implicit solvent, altered thermodn. properties of a box of water mols., and changes in the transition free energies between dihedral angle conformations. Finally, in the case of strong thermocoupling, we link the obsd. artifacts to previous work in nonlinear dynamics and show that it is possible to drive a 20-residue, implicitly solvated protein into periodic trajectories if the thermostat is not used properly. The authors' findings should help other investigators re-evaluate simulations that may were corrupted and obtain more accurate results.
- 60Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.; Klein, M. L. Comparison of Simple Potential Functions for Simulating Liquid Water J. Chem. Phys. 1983, 79 (2) 926 DOI: 10.1063/1.44586960https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3sXksF2htL4%253D&md5=a1161334e381746be8c9b15a5e56f704Comparison of simple potential functions for simulating liquid waterJorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D.; Impey, Roger W.; Klein, Michael L.Journal of Chemical Physics (1983), 79 (2), 926-35CODEN: JCPSA6; ISSN:0021-9606.Classical Monte Carlo simulations were carried out for liq. H2O in the NPT ensemble at 25° and 1 atm using 6 of the simpler intermol. potential functions for the dimer. Comparisons were made with exptl. thermodn. and structural data including the neutron diffraction results of Thiessen and Narten (1982). The computed densities and potential energies agree with expt. except for the original Bernal-Fowler model, which yields an 18% overest. of the d. and poor structural results. The discrepancy may be due to the correction terms needed in processing the neutron data or to an effect uniformly neglected in the computations. Comparisons were made for the self-diffusion coeffs. obtained from mol. dynamics simulations.
- 61Ryckaert, J. P.; Ciccotti, G.; Berendsen, H. J. C. Numerical-Integration of Cartesian Equations of Motion of a System with Constraints - Molecular-Dynamics of N-Alkanes J. Comput. Phys. 1977, 23, 327– 341 DOI: 10.1016/0021-9991(77)90098-561https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2sXktVGhsL4%253D&md5=b4aecddfde149117813a5ea4f5353ce2Numerical integration of the Cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanesRyckaert, Jean Paul; Ciccotti, Giovanni; Berendsen, Herman J. C.Journal of Computational Physics (1977), 23 (3), 327-41CODEN: JCTPAH; ISSN:0021-9991.A numerical algorithm integrating the 3N Cartesian equation of motion of a system of N points subject to holonomic constraints is applied to mol. dynamics simulation of a liq. of 64 butane mols.
- 62Darden, T.; York, D.; Pedersen, L. Particle Mesh Ewald: An N log(N) Method for Ewald Sums in Large Systems J. Chem. Phys. 1993, 98 (12) 10089 DOI: 10.1063/1.46439762https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXks1Ohsr0%253D&md5=3c9f230bd01b7b714fd096d4d2e755f6Particle mesh Ewald: an N·log(N) method for Ewald sums in large systemsDarden, Tom; York, Darrin; Pedersen, LeeJournal of Chemical Physics (1993), 98 (12), 10089-92CODEN: JCPSA6; ISSN:0021-9606.An N·log(N) method for evaluating electrostatic energies and forces of large periodic systems is presented. The method is based on interpolation of the reciprocal space Ewald sums and evaluation of the resulting convolution using fast Fourier transforms. Timings and accuracies are presented for three large cryst. ionic systems.
- 63Bennett, C. H. Efficient Estimation of Free Energy Differences from Monte Carlo Data J. Comput. Phys. 1976, 22 (2) 245– 268 DOI: 10.1016/0021-9991(76)90078-4There is no corresponding record for this reference.
- 64Shirts, M. R.; Chodera, J. D. Statistically Optimal Analysis of Samples from Multiple Equilibrium States J. Chem. Phys. 2008, 129 (12) 124105 DOI: 10.1063/1.297817764https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1WnsL7F&md5=479183e1f45fc58dd7c6e5ef1e73d45dStatistically optimal analysis of samples from multiple equilibrium statesShirts, Michael R.; Chodera, John D.Journal of Chemical Physics (2008), 129 (12), 124105/1-124105/10CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)We present a new estimator for computing free energy differences and thermodn. expectations as well as their uncertainties from samples obtained from multiple equil. states via either simulation or expt. The estimator, which we call the multistate Bennett acceptance ratio estimator (MBAR) because it reduces to the Bennett acceptance ratio estimator (BAR) when only two states are considered, has significant advantages over multiple histogram reweighting methods for combining data from multiple states. It does not require the sampled energy range to be discretized to produce histograms, eliminating bias due to energy binning and significantly reducing the time complexity of computing a soln. to the estg. equations in many cases. Addnl., an est. of the statistical uncertainty is provided for all estd. quantities. In the large sample limit, MBAR is unbiased and has the lowest variance of any known estimator for making use of equil. data collected from multiple states. We illustrate this method by producing a highly precise est. of the potential of mean force for a DNA hairpin system, combining data from multiple optical tweezer measurements under const. force bias. (c) 2008 American Institute of Physics.
- 65O’Boyle, N. M.; Banck, M.; James, C. A.; Morley, C.; Vandermeersch, T.; Hutchison, G. R. Open Babel: An Open Chemical Toolbox J. Cheminf. 2011, 3 (1) 33 DOI: 10.1186/1758-2946-3-3365https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVWjurbF&md5=74e4f19b7f87417f916d57f7abcfb761Open Babel: an open chemical toolboxO'Boyle, Noel M.; Banck, Michael; James, Craig A.; Morley, Chris; Vandermeersch, Tim; Hutchison, Geoffrey R.Journal of Cheminformatics (2011), 3 (), 33CODEN: JCOHB3; ISSN:1758-2946. (Chemistry Central Ltd.)Background: A frequent problem in computational modeling is the interconversion of chem. structures between different formats. While std. interchange formats exist (for example, Chem. Markup Language) and de facto stds. have arisen (for example, SMILES format), the need to interconvert formats is a continuing problem due to the multitude of different application areas for chem. data, differences in the data stored by different formats (0D vs. 3D, for example), and competition between software along with a lack of vendor-neutral formats. Results: We discuss, for the first time, Open Babel, an open-source chem. toolbox that speaks the many languages of chem. data. Open Babel version 2.3 interconverts over 110 formats. The need to represent such a wide variety of chem. and mol. data requires a library that implements a wide range of cheminformatics algorithms, from partial charge assignment and aromaticity detection, to bond order perception and canonicalization. We detail the implementation of Open Babel, describe key advances in the 2.3 release, and outline a variety of uses both in terms of software products and scientific research, including applications far beyond simple format interconversion. Conclusions: Open Babel presents a soln. to the proliferation of multiple chem. file formats. In addn., it provides a variety of useful utilities from conformer searching and 2D depiction, to filtering, batch conversion, and substructure and similarity searching. For developers, it can be used as a programming library to handle chem. data in areas such as org. chem., drug design, materials science, and computational chem. It is freely available under an open-source license.
- 66Vanommeslaeghe, K.; MacKerell, A. D. Automation of the CHARMM General Force Field (CGenFF) I: Bond Perception and Atom Typing J. Chem. Inf. Model. 2012, 52 (12) 3144– 3154 DOI: 10.1021/ci300363c66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1Gns7fL&md5=c6679293f4a2501f2bcadf2020ca1473Automation of the CHARMM General Force Field (CGenFF) I: Bond Perception and Atom TypingVanommeslaeghe, K.; MacKerell, A. D.Journal of Chemical Information and Modeling (2012), 52 (12), 3144-3154CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)Mol. mechanics force fields are widely used in computer-aided drug design for the study of drug-like mols. alone or interacting with biol. systems. In simulations involving biol. macromols., the biol. part is typically represented by a specialized biomol. force field, while the drug is represented by a matching general (org.) force field. In order to apply these general force fields to an arbitrary drug-like mol., functionality for assignment of atom types, parameters, and charges is required. In the present article, which is part I of a series of two, we present the algorithms for bond perception and atom typing for the CHARMM General Force Field (CGenFF). The CGenFF atom typer first assocs. attributes to the atoms and bonds in a mol., such as valence, bond order, and ring membership among others. Of note are a no. of features that are specifically required for CGenFF. This information is then used by the atom typing routine to assign CGenFF atom types based on a programmable decision tree. This allows for straight-forward implementation of CGenFF's complicated atom typing rules and for equally straight-forward updating of the atom typing scheme as the force field grows. The presented atom typer was validated by assigning correct atom types on 477 model compds. including in the training set as well as 126 test-set mols. that were constructed to specifically verify its different components. The program may be utilized via an online implementation at https://www.paramchem.org/.
- 67Cieplak, P.; Cornell, W. D.; Bayly, C.; Kollman, P. A. Application of the Multimolecule and Multiconformational RESP Methodology to Biopolymers: Charge Derivation for DNA, RNA, and Proteins J. Comput. Chem. 1995, 16 (11) 1357– 1377 DOI: 10.1002/jcc.54016110667https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXovVKqtrY%253D&md5=27e75f5f3f53d777737661e591e957cdApplication of the multimolecule and multiconformational RESP methodology to biopolymers: charge derivation for DNA, RNA, and proteinsCieplak, Piotr; Cornell, Wendy D.; Bayly, Christopher; Kollman, Peter A.Journal of Computational Chemistry (1995), 16 (11), 1357-77CODEN: JCCHDD; ISSN:0192-8651. (Wiley)The authors present the derivation of charges of ribo- and deoxynucleosides, nucleotides, and peptide fragments using electrostatic potentials obtained from ab initio calcns. with the 6-31G* basis set. For the nucleic acid fragments, the authors used electrostatic potentials of the four deoxyribonucleoside (A, G, C, T) and four ribonucleosides (A, G, C, U) and dimethylphosphate. The charges for the deoxyribose nucleosides and nucleotides are derived using multiple-mol. fitting and restrained electrostatic potential (RESP) fits, with Lagrangian multipliers ensuring a net charge of 0 or. The authors suggest that the preferred approach for deriving charges for nucleosides and nucleotides involves allowing only C1' and H1' of the sugar to vary as the nucleic acid base, with the remainder of sugar and backbone atoms forced to be equiv. For peptide fragments, the authors have combined multiple conformation fitting, previously employed by Williams and Reynolds et al., with the RESP approach to derive charges for blocked dipeptides appropriate for each of the 20 naturally occurring amino acids. Based on the results for Pr amine, the authors suggest that two conformations for each peptide suffice to give charges that represent well the conformationally dependent electrostatic properties of mols., provided that these two conformations contain different values of the dihedral angles that terminate in heteroatoms or hydrogens attached to heteroatoms or hydrogens attached to heteroatoms. In these blocked dipeptide models, it is useful to require equiv. N-H and C=O charges for all amino acids with a given net charge (except proline), and this is accomplished in a straightforward fashion with multiple-mol. fitting. Finally, the application of multiple Lagrangian constraints allows for the derivation of monomeric residues with the appropriate net charge from a chem. blocked version of the residue. The multiple Lagrange constraints also enable charges from two or more mols. to be spliced together in a well-defined fashion. Thus, the combined use of multiple mols., multiple conformations, multiple Lagrangian constraints, and RESP fitting is shown to be a powerful approach to deriving electrostatic charges for biopolymers.
- 68Dupradeau, F.-Y.; Pigache, A.; Zaffran, T.; Savineau, C.; Lelong, R.; Grivel, N.; Lelong, D.; Rosanski, W.; Cieplak, P. The R.E.D. Tools: Advances in RESP and ESP Charge Derivation and Force Field Library Building Phys. Chem. Chem. Phys. 2010, 12 (28) 7821– 7839 DOI: 10.1039/c0cp00111b68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXosFaqtrk%253D&md5=845cc10ea7ed2f0222361db82bd80e39The R.E.D. tools: advances in RESP and ESP charge derivation and force field library buildingDupradeau, Francois-Yves; Pigache, Adrien; Zaffran, Thomas; Savineau, Corentin; Lelong, Rodolphe; Grivel, Nicolas; Lelong, Dimitri; Rosanski, Wilfried; Cieplak, PiotrPhysical Chemistry Chemical Physics (2010), 12 (28), 7821-7839CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)Deriving at. charges and building a force field library for a new mol. are key steps when developing a force field required for conducting structural and energy-based anal. using mol. mechanics. Derivation of popular RESP charges for a set of residues is a complex and error prone procedure because it depends on numerous input parameters. To overcome these problems, the R.E.D. Tools (RESP and ESP charge Derive, http://q4md-forcefieldtools.org/RED/) have been developed to perform charge derivation in an automatic and straightforward way. The R.E.D. program handles chem. elements up to bromine in the periodic table. It interfaces different quantum mech. programs employed for geometry optimization and computing mol. electrostatic potential(s), and performs charge fitting using the RESP program. By defining tight optimization criteria and by controlling the mol. orientation of each optimized geometry, charge values are reproduced at any computer platform with an accuracy of 0.0001 e. The charges can be fitted using multiple conformations, making them suitable for mol. dynamics simulations. R.E.D. allows also for defining charge constraints during multiple mol. charge fitting, which are used to derive charges for mol. fragments. Finally, R.E.D. incorporates charges into a force field library, readily usable in mol. dynamics computer packages. For complex cases, such as a set of homologous mols. belonging to a common family, an entire force field topol. database is generated. Currently, the at. charges and force field libraries have been developed for more than fifty model systems and stored in the RESP ESP charge DDataBase. Selected results related to non-polarizable charge models are presented and discussed.
- 69Kramer, C.; Gedeck, P.; Meuwly, M. Atomic Multipoles: Electrostatic Potential Fit, Local Reference Axis Systems, and Conformational Dependence J. Comput. Chem. 2012, 33 (20) 1673– 1688 DOI: 10.1002/jcc.2299669https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmtlWjtbw%253D&md5=5d91f01ab9b5dfabf5736a367b2af766Atomic multipoles: Electrostatic potential fit, local reference axis systems, and conformational dependenceKramer, Christian; Gedeck, Peter; Meuwly, MarkusJournal of Computational Chemistry (2012), 33 (20), 1673-1688CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)Currently, all std. force fields for biomol. simulations use point charges to model intermol. electrostatic interactions. This is a fast and simple approach but has deficiencies when the electrostatic potential (ESP) is compared to that from ab initio methods. Here, we show how at. multipoles can be rigorously implemented into common biomol. force fields. For this, a comprehensive set of local ref. axis systems is introduced, which represents a universal soln. for treating atom-centered multipoles for all small org. mols. and proteins. Furthermore, we introduce a new method for fitting at. multipole moments to the quantum mech. derived ESP. This methods yields a 50-90% error redn. compared to both point charges fit to the ESP and multipoles directly calcd. from the ab initio electron d. It is shown that it is necessary to directly fit the multipole moments of conformational ensembles to the ESP. Ignoring the conformational dependence or averaging over parameters from different conformations dramatically deteriorates the results obtained with at. multipole moments, rendering multipoles worse than partial charges. © 2012 Wiley Periodicals, Inc.
- 70Reynolds, C. A.; Essex, J. W.; Richards, W. G. Atomic Charges for Variable Molecular Conformations J. Am. Chem. Soc. 1992, 114 (23) 9075– 9079 DOI: 10.1021/ja00049a04570https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XmtFWkt78%253D&md5=47e939c97e4880a8fcb33fed44832b4aAtomic charges for variable molecular conformationsReynolds, Christopher A.; Essex, Jonathan W.; Richards, W. GrahamJournal of the American Chemical Society (1992), 114 (23), 9075-9CODEN: JACSAT; ISSN:0002-7863.The problem of generating high-quality at. charges valid over a range of conformations has been addressed using two related methods which both employ a constrained minimization of the difference between the quantum mech. and classical MEP (mol. electrostatic potential) with respect to the at. charges. The first method involves detg. the MEP and constraining the charges to reproduce the dipole at an alternative geometry. The second method involves detg. the MEP for each conformation of interest and weighting the MEP for each conformation according to the appropriate Boltzmann factor. These methods offer considerable improvement over averaging the charges obtained at each conformation. The improvement in the performance of these multiple conformation MEP derived charges is illustrated by studying the variation of the classical dipole with conformation and comparing the results with those from ab initio calcns. It is proposed that the main use of these multiple conformation MEP derived charges and dipole constrained charges is likely to be in computer simulations where the ability to search conformational space is matched by the ability of the charges to yield the correct electrostatic properties at the conformations of interest. The errors arising from ignoring these effects have been assessed by evaluating the hydration free energy using a continuum method and are found to be significant. The extension of these methods to protein simulations is discussed.
- 71Kramer, C.; Gedeck, P.; Meuwly, M. Multipole-Based Force Fields from Ab Initio Interaction Energies and the Need for Jointly Refitting All Intermolecular Parameters J. Chem. Theory Comput. 2013, 9 (3) 1499– 1511 DOI: 10.1021/ct300888f71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXis12ltbc%253D&md5=1a5aaefd41c10333f9666cc1853c28aeMultipole-Based Force Fields from ab Initio Interaction Energies and the Need for Jointly Refitting All Intermolecular ParametersKramer, Christian; Gedeck, Peter; Meuwly, MarkusJournal of Chemical Theory and Computation (2013), 9 (3), 1499-1511CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)Distributed at. multipole (MTP) moments promise significant improvements over point charges (PCs) in mol. force fields, as they (a) more realistically reproduce the ab initio electrostatic potential (ESP) and (b) allow to capture anisotropic at. properties such as lone pairs, conjugated systems, and σ holes. The present work focuses on the question of whether multipolar electrostatics instead of PCs in std. force fields leads to quant. improvements over point charges in reproducing intermol. interactions. To this end, the interaction energies of two model systems, benzonitrile (BZN) and formamide (FAM) homodimers, are characterized over a wide range of dimer conformations. It is found that although with MTPs the monomer ab initio ESP can be captured better by about an order of magnitude compared to point charges (PCs), this does not directly translate into better describing ab initio interaction energies compared to PCs. Neither ESP-fitted MTPs nor refitted Lennard-Jones (LJ) parameters alone demonstrate a clear superiority of at. MTPs. We show that only if both electrostatic and LJ parameters are jointly optimized in std., nonpolarizable force fields, at. are MTPs clearly beneficial for reproducing ab initio dimerization energies. After an exhaustive exponent scan, we find that for both BZN and FAM, at. MTPs and a 9-6 LJ potential can reproduce ab initio interaction energies with ∼30% (RMSD 0.13 vs 0.18 kcal/mol) less error than point charges (PCs) and a 12-6 LJ potential. We also find that the improvement due to using MTPs with a 9-6 LJ potential is considerably more pronounced than with a 12-6 LJ potential (≈ 10%; RMSD 0.19 vs. 0.21 kcal/mol).
- 72Wang, L.-P.; Chen, J.; Van Voorhis, T. Systematic Parametrization of Polarizable Force Fields from Quantum Chemistry Data J. Chem. Theory Comput. 2013, 9 (1) 452– 460 DOI: 10.1021/ct300826t72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslSmtrbO&md5=f6781aa8e4ba50dfb8ca3a0582bafae0Systematic Parametrization of Polarizable Force Fields from Quantum Chemistry DataWang, Lee-Ping; Chen, Jiahao; Van Voorhis, TroyJournal of Chemical Theory and Computation (2013), 9 (1), 452-460CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)We introduce ForceBalance, a method and free software package for systematic force field optimization with the ability to parametrize a wide variety of functional forms using flexible combinations of ref. data. We outline several important challenges in force field development and how they are addressed in ForceBalance, and present an example calcn. where these methods are applied to develop a highly accurate polarizable water model. ForceBalance is available for free download at https://simtk.org/home/forcebalance.
- 73Wang, L.-P.; Martinez, T. J.; Pande, V. S. Building Force Fields: An Automatic, Systematic, and Reproducible Approach J. Phys. Chem. Lett. 2014, 5 (11) 1885– 1891 DOI: 10.1021/jz500737m73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXnvV2htrs%253D&md5=0b901b4ef8949839df5b5e3e36e38424Building Force Fields: An Automatic, Systematic, and Reproducible ApproachWang, Lee-Ping; Martinez, Todd J.; Pande, Vijay S.Journal of Physical Chemistry Letters (2014), 5 (11), 1885-1891CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)The development of accurate mol. mechanics force fields is a significant challenge that must be addressed for the continued success of mol. simulation. We developed the ForceBalance method to automatically derive accurate force field parameters using flexible combinations of exptl. and theor. ref. data. The method is demonstrated in the parametrization of two rigid water models, yielding new parameter sets (TIP3P-FB and TIP4P-FB) that accurately describe many phys. properties of water.
- 74Mobley, D. L.; Bayly, C. I.; Cooper, M. D.; Shirts, M. R.; Dill, K. A. Small Molecule Hydration Free Energies in Explicit Solvent: An Extensive Test of Fixed-Charge Atomistic Simulations J. Chem. Theory Comput. 2009, 5 (2) 350– 358 DOI: 10.1021/ct800409d74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXps1Om&md5=df247d489cd56a27d28e842ea2a4c914Small Molecule Hydration Free Energies in Explicit Solvent: An Extensive Test of Fixed-Charge Atomistic SimulationsMobley, David L.; Bayly, Christopher I.; Cooper, Matthew D.; Shirts, Michael R.; Dill, Ken A.Journal of Chemical Theory and Computation (2009), 5 (2), 350-358CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)Using mol. dynamics free energy simulations with TIP3P explicit solvent, the authors compute the hydration free energies of 504 neutral small org. mols. and compare them to expts. They find, first, good general agreement between the simulations and the expts., with an rms error of 1.24 kcal/mol over the whole set (i.e., about 2 kT) and a correlation coeff. of 0.89. Second, they use an automated procedure to identify systematic errors for some classes of compds. and suggest some improvements to the force field. Alkyne hydration free energies are particularly poorly predicted due to problems with a Lennard-Jones well depth and an alternate choice for this well depth largely rectifies the situation. Third, they study the nonpolar component of hydration free energies; i.e., the part that is not due to electrostatics. While repulsive and attractive components of the nonpolar part both scale roughly with surface area (or vol.) of the solute, the total nonpolar free energy does not scale with the solute surface area or vol. because it is a small difference between large components and is dominated by the deviations from the trend. While the methods used here are not new, this is a more extensive test than previous explicit solvent studies, and the size of the test set allows identification of systematic problems with force field parameters for particular classes of compds.
- 75Baker, C. M.; Mackerell, A. D. Polarizability Rescaling and Atom-Based Thole Scaling in the CHARMM Drude Polarizable Force Field for Ethers J. Mol. Model. 2010, 16 (3) 567– 576 DOI: 10.1007/s00894-009-0572-475https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlslGht7k%253D&md5=7798366fb1fb8eed594bb090a17326e1Polarizability rescaling and atom-based Thole scaling in the CHARMM Drude polarizable force field for ethersBaker, Christopher M.; MacKerell, Alexander D., Jr.Journal of Molecular Modeling (2010), 16 (3), 567-576CODEN: JMMOFK; ISSN:0948-5023. (Springer GmbH)Within the CHARMM polarizable force field based on the classical Drude oscillator, at. polarizabilities are derived via fitting to ab initio calcd. data on isolated gas phase mols., with an empirical scaling factor applied to account for differences between the gas and condensed phases. In the development of polarizable models for the ethers, a polarizability scaling factor of 0.7 was previously applied. While the resulting force field models gave good agreement with a variety of exptl. data, they systematically underestimated the liq. phase dielec. consts. Here, a new CHARMM polarizable model is developed for the ethers, employing a polarizability scaling factor of 0.85 and including atom-based Thole scale factors recently introduced into the CHARMM Drude polarizable force field. The new model offers a significant improvement in the reprodn. of liq. phase dielec. consts., while maintaining the good agreement of the previous model with all other exptl. and quantum mech. data, highlighting the sensitivity of liq. phase properties to the choice of at. polarizability parameters.
- 76Lopes, P. E. M.; Lamoureux, G.; Mackerell, A. D. Polarizable Empirical Force Field for Nitrogen-Containing Heteroaromatic Compounds Based on the Classical Drude Oscillator J. Comput. Chem. 2009, 30 (12) 1821– 1838 DOI: 10.1002/jcc.21183There is no corresponding record for this reference.
- 77Tukey, J. W. Comparing Individual Means in the Analysis of Variance Biometrics 1949, 5 (2) 99 DOI: 10.2307/300191377https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaH1M%252FltlGgsA%253D%253D&md5=b97aa1acbc9e08776e6d2778f1328fdaComparing individual means in the analysis of varianceTUKEY J WBiometrics (1949), 5 (2), 99-114 ISSN:0006-341X.There is no expanded citation for this reference.
- 78Bradshaw, R. T.; Essex, J. W. Supplementary underlying data for “Evaluating parameterization protocols for hydration free energy calculations with the AMOEBA polarizable force field” http://dx.doi.org/10.5281/zenodo.54959.There is no corresponding record for this reference.
- 79Wang, L.-P.; Chen, J.; Van Voorhis, T. Systematic Parametrization of Polarizable Force Fields from Quantum Chemistry Data J. Chem. Theory Comput. 2013, 9 (1) 452– 460 DOI: 10.1021/ct300826t79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslSmtrbO&md5=f6781aa8e4ba50dfb8ca3a0582bafae0Systematic Parametrization of Polarizable Force Fields from Quantum Chemistry DataWang, Lee-Ping; Chen, Jiahao; Van Voorhis, TroyJournal of Chemical Theory and Computation (2013), 9 (1), 452-460CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)We introduce ForceBalance, a method and free software package for systematic force field optimization with the ability to parametrize a wide variety of functional forms using flexible combinations of ref. data. We outline several important challenges in force field development and how they are addressed in ForceBalance, and present an example calcn. where these methods are applied to develop a highly accurate polarizable water model. ForceBalance is available for free download at https://simtk.org/home/forcebalance.
- 80Wang, L.-P.; Head-Gordon, T.; Ponder, J. W.; Ren, P.; Chodera, J. D.; Eastman, P. K.; Martinez, T. J.; Pande, V. S. Systematic Improvement of a Classical Molecular Model of Water J. Phys. Chem. B 2013, 117 (34) 9956– 9972 DOI: 10.1021/jp403802c80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXptFehtrs%253D&md5=ab76a694e55ac1a916ef2a75ff749673Systematic Improvement of a Classical Molecular Model of WaterWang, Lee-Ping; Head-Gordon, Teresa; Ponder, Jay W.; Ren, Pengyu; Chodera, John D.; Eastman, Peter K.; Martinez, Todd J.; Pande, Vijay S.Journal of Physical Chemistry B (2013), 117 (34), 9956-9972CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)We report the iAMOEBA (inexpensive AMOEBA) classical polarizable water model. The iAMOEBA model uses a direct approxn. to describe electronic polarizability, in which the induced dipoles are detd. directly from the permanent multipole elec. fields and do not interact with one another. The direct approxn. reduces the computational cost relative to a fully self-consistent polarizable model such as AMOEBA. The model is parameterized using ForceBalance, a systematic optimization method that simultaneously utilizes training data from exptl. measurements and high-level ab initio calcns. We show that iAMOEBA is a highly accurate model for water in the solid, liq., and gas phases, with the ability to fully capture the effects of electronic polarization and predict a comprehensive set of water properties beyond the training data set including the phase diagram. The increased accuracy of iAMOEBA over the fully polarizable AMOEBA model demonstrates ForceBalance as a method that allows the researcher to systematically improve empirical models by efficiently utilizing the available data.
- 81Qi, R.; Wang, L.-P.; Wang, Q.; Pande, V. S.; Ren, P. United Polarizable Multipole Water Model for Molecular Mechanics Simulation J. Chem. Phys. 2015, 143 (1) 014504 DOI: 10.1063/1.492333881https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFCjt7vL&md5=b146814ebdf8fe690c22905a32657188United polarizable multipole water model for molecular mechanics simulationQi, Rui; Wang, Lee-Ping; Wang, Qiantao; Pande, Vijay S.; Ren, PengyuJournal of Chemical Physics (2015), 143 (1), 014504/1-014504/12CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)We report the development of a united AMOEBA (uAMOEBA) polarizable water model, which is computationally 3-5 times more efficient than the three-site AMOEBA03 model in mol. dynamics simulations while providing comparable accuracy for gas-phase and liq. properties. In this coarse-grained polarizable water model, both electrostatic (permanent and induced) and van der Waals representations have been reduced to a single site located at the oxygen atom. The permanent charge distribution is described via the mol. dipole and quadrupole moments and the many-body polarization via an isotropic mol. polarizability, all located at the oxygen center. Similarly, a single van der Waals interaction site is used for each water mol. Hydrogen atoms are retained only for the purpose of defining local frames for the mol. multipole moments and intramol. vibrational modes. The parameters have been derived based on a combination of ab initio quantum mech. and exptl. data set contg. gas-phase cluster structures and energies, and liq. thermodn. properties. For validation, addnl. properties including dimer interaction energy, liq. structures, self-diffusion coeff., and shear viscosity have been evaluated. The results demonstrate good transferability from the gas to the liq. phase over a wide range of temps., and from nonpolar to polar environments, due to the presence of mol. polarizability. The water coordination, hydrogen-bonding structure, and dynamic properties given by uAMOEBA are similar to those derived from the all-atom AMOEBA03 model and expts. Thus, the current model is an accurate and efficient alternative for modeling water. (c) 2015 American Institute of Physics.
- 82Bradshaw, R. T.; Essex, J. W. Underlying data for “Evaluating parameterization protocols for hydration free energy calculations with the AMOEBA polarizable force field” http://dx.doi.org/10.5281/zenodo.35586.There is no corresponding record for this reference.
Supporting Information
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jctc.6b00276.
Full details of AMOEBA parametrization choices and methods for each parameter set, all SAMPL4 solute structures and details of manually defined solute polarization groups, comparison of solute RMSD between parameter sets 2 and 3, definitions of solute subgroups, statistical p values for the ANOVA test between solute HFE predictions with different methods, and a summary of pairwise significant differences between solute results across parameter sets are available (PDF)
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