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Analytical Model of the Free Energy of Alchemical Molecular Binding

  • Denise Kilburg
    Denise Kilburg
    Department of Chemistry, Brooklyn College of the City University of New York, Brooklyn, New York 11210, United States
    Ph.D. Program in Chemistry, Graduate Center of the City University of New York, New York, New York 10016, United States
  •  and 
  • Emilio Gallicchio*
    Emilio Gallicchio
    Department of Chemistry, Brooklyn College of the City University of New York, Brooklyn, New York 11210, United States
    Ph.D. Program in Chemistry  and  Ph.D. Program in Biochemistry, Graduate Center of the City University of New York, New York, New York 10016, United States
    *E-mail: [email protected]
Cite this: J. Chem. Theory Comput. 2018, 14, 12, 6183–6196
Publication Date (Web):November 12, 2018
https://doi.org/10.1021/acs.jctc.8b00967
Copyright © 2018 American Chemical Society

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    Abstract

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    We present a parametrized analytic statistical model of the thermodynamics of alchemical molecular binding within the solvent potential of mean force formalism. The model describes the free energy profiles of linear single-decoupling alchemical binding free energy calculations accurately. The parameters of the model, which are physically motivated, are derived by maximum likelihood inference from data obtained from alchemical molecular simulations. The validity of the model has been assessed on a set of host–guest complexes. The model faithfully reproduces both the binding free energy profiles and the probability densities of the perturbation energy as a function of the alchemical progress parameter. The model offers a rationalization for the characteristic shape of binding free energy profiles. The parameters obtained from the model are potentially useful descriptors of the association equilibrium of molecular complexes. Potential applications of the model for the classification of molecular complexes and the design of alchemical molecular simulations are envisioned.

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    Cited By

    This article is cited by 6 publications.

    1. Solmaz Azimi, Sheenam Khuttan, Joe Z. Wu, Rajat K. Pal, Emilio Gallicchio. Relative Binding Free Energy Calculations for Ligands with Diverse Scaffolds with the Alchemical Transfer Method. Journal of Chemical Information and Modeling 2022, 62 (2) , 309-323. https://doi.org/10.1021/acs.jcim.1c01129
    2. Joe Z. Wu, Solmaz Azimi, Sheenam Khuttan, Nanjie Deng, Emilio Gallicchio. Alchemical Transfer Approach to Absolute Binding Free Energy Estimation. Journal of Chemical Theory and Computation 2021, 17 (6) , 3309-3319. https://doi.org/10.1021/acs.jctc.1c00266
    3. Jeffrey Cruz, Lauren Wickstrom, Danzhou Yang, Emilio Gallicchio, Nanjie Deng. Combining Alchemical Transformation with a Physical Pathway to Accelerate Absolute Binding Free Energy Calculations of Charged Ligands to Enclosed Binding Sites. Journal of Chemical Theory and Computation 2020, 16 (4) , 2803-2813. https://doi.org/10.1021/acs.jctc.9b01119
    4. Sheenam Khuttan, Solmaz Azimi, Joe Z. Wu, Emilio Gallicchio. Alchemical transformations for concerted hydration free energy estimation with explicit solvation. The Journal of Chemical Physics 2021, 154 (5) https://doi.org/10.1063/5.0036944
    5. Caroline Desgranges, Jerome Delhommelle. Towards a machine learned thermodynamics: exploration of free energy landscapes in molecular fluids, biological systems and for gas storage and separation in metal–organic frameworks. Molecular Systems Design & Engineering 2021, 6 (1) , 52-65. https://doi.org/10.1039/D0ME00134A
    6. Rajat K. Pal, Emilio Gallicchio. Perturbation potentials to overcome order/disorder transitions in alchemical binding free energy calculations. The Journal of Chemical Physics 2019, 151 (12) https://doi.org/10.1063/1.5123154

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