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Charge Transfer and Polarization for Chloride Ions Bound in ClC Transport Proteins: Natural Bond Orbital and Energy Decomposition Analyses

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    Charge Transfer and Polarization for Chloride Ions Bound in ClC Transport Proteins: Natural Bond Orbital and Energy Decomposition Analyses
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    Chemistry Department, University of Colorado Denver, Denver, Colorado 80217-3364, United States
    *E-mail: [email protected]. Phone: 303-352-3889. Fax: 303-556-4776.
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    The Journal of Physical Chemistry B

    Cite this: J. Phys. Chem. B 2013, 117, 50, 16029–16043
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    https://doi.org/10.1021/jp409306x
    Published November 21, 2013
    Copyright © 2013 American Chemical Society
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    Abstract

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    ClC transport proteins show a distinct “broken-helix” architecture, in which certain α-helices are oriented with their N-terminal ends pointed toward the binding sites where the chloride ions are held extensively by the backbone amide nitrogen atoms from the helices. To understand the effectiveness of such binding structures, we carried out natural bond orbital analysis and energy decomposition analysis employing truncated active-site model systems for the bound chloride ions along the translocation pore of the EcClC proteins. Our results indicated that the chloride ions are stabilized in such a binding environment by electrostatic, polarization, and charge-transfer interactions with the backbone and a few side chains. Up to ∼25% of the formal charges of the chloride ions were found smeared out to the surroundings primarily via charge transfer from the chloride’s lone pair n(Cl) orbitals to the protein’s antibonding σ*(N–H) or σ*(O–H) orbitals; those σ* orbitals are localized at the polar N–H and O–H bonds in the chloride’s first solvation shells formed by the backbone amide groups and the side chains of residues Ser107, Arg147, Glu148, and Tyr445. Polarizations by the chloride ions were dominated by the redistribution of charge densities among the π orbitals and lone pair orbitals of the protein atoms, in particular the atoms of the backbone peptide links and of the side chains of Arg147, Glu148, and Tyr445. The substantial amounts of electron density involved in charge transfer and in polarization were consistent with the large energetic contributions by the two processes revealed by the energy decomposition analysis. The significant polarization and charge-transfer effects may have impacts on the mechanisms and dynamics of the chloride transport by the ClC proteins.

    Copyright © 2013 American Chemical Society

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    Supporting Information

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    Details about the extrapolation of the MP2 energies and about the construction of the ClC active-site models; additional chloride–amino acid model complexes not included in Figure 2 (Figure S1) and the WT_Cl2, PWT_Cl3, PWT_Cl4, and E148Q_Cl3 active-site models (Figure S2); NEDA and NBO analysis by M06-2X calculations for the chloride–amino acid model complexes in Figure 2 (Tables S1 and S2); results for the additional chloride–amino acid model complexes in Tables S3 (KM-EDA), S4 (NEDA by B3LYP), S5 (NEDA by M06-2X), S6 (NBO analysis by B3LYP), and S7 (NBO analysis by M06-2X); NEDA and NBO analysis by M06-2X calculations for the ClC active-site models (Tables S8 and S9, respectively); sequence alignment for R147 in EcClC and its equivalents in the ClC family of proteins (Table S10); and Cartesian coordinates of all the chloride–amino acid complexes and of all the active-site models (Tables S11 and S12, respectively). This material is available free of charge via the Internet at http://pubs.acs.org.

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    This article is cited by 12 publications.

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    6. Heather B. Mayes, Sangyun Lee, Andrew D. White, Gregory A. Voth, and Jessica M. J. Swanson . Multiscale Kinetic Modeling Reveals an Ensemble of Cl–/H+ Exchange Pathways in ClC-ec1 Antiporter. Journal of the American Chemical Society 2018, 140 (5) , 1793-1804. https://doi.org/10.1021/jacs.7b11463
    7. M. J. S. Phipps, T. Fox, C. S. Tautermann, and C.-K. Skylaris . Intuitive Density Functional Theory-Based Energy Decomposition Analysis for Protein–Ligand Interactions. Journal of Chemical Theory and Computation 2017, 13 (4) , 1837-1850. https://doi.org/10.1021/acs.jctc.6b01230
    8. Zhihong Chen and Thomas L. Beck . Free Energies of Ion Binding in the Bacterial CLC-ec1 Chloride Transporter with Implications for the Transport Mechanism and Selectivity. The Journal of Physical Chemistry B 2016, 120 (12) , 3129-3139. https://doi.org/10.1021/acs.jpcb.6b01150
    9. Soroosh Pezeshki, Christal Davis, Andreas Heyden, and Hai Lin . Adaptive-Partitioning QM/MM Dynamics Simulations: 3. Solvent Molecules Entering and Leaving Protein Binding Sites. Journal of Chemical Theory and Computation 2014, 10 (11) , 4765-4776. https://doi.org/10.1021/ct500553x
    10. Somayeh Asgharpour, L. América Chi, Marc Spehr, Paolo Carloni, Mercedes Alfonso-Prieto. Fluoride Transport and Inhibition Across CLC Transporters. 2022, 81-100. https://doi.org/10.1007/164_2022_593
    11. Chun-Hung Wang, Adam W. Duster, Baris O. Aydintug, MacKenzie G. Zarecki, Hai Lin. Chloride Ion Transport by the E. coli CLC Cl−/H+ Antiporter: A Combined Quantum-Mechanical and Molecular-Mechanical Study. Frontiers in Chemistry 2018, 6 https://doi.org/10.3389/fchem.2018.00062
    12. Maximillian J. S. Phipps, Thomas Fox, Christofer S. Tautermann, Chris-Kriton Skylaris. Energy decomposition analysis approaches and their evaluation on prototypical protein–drug interaction patterns. Chemical Society Reviews 2015, 44 (10) , 3177-3211. https://doi.org/10.1039/C4CS00375F
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    The Journal of Physical Chemistry B

    Cite this: J. Phys. Chem. B 2013, 117, 50, 16029–16043
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jp409306x
    Published November 21, 2013
    Copyright © 2013 American Chemical Society
    Request reuse permissions

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