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Title: Chloride Ion Transport by the E. coli CLC Cl–/H+ Antiporter: A Combined Quantum-Mechanical and Molecular-Mechanical Study

Abstract

We performed steered molecular dynamics (SMD) and umbrella sampling simulations of Cl– ion migration through the transmembrane domain of a prototypical E. coli CLC Cl–/H+ antiporter by employing combined quantum-mechanical (QM) and molecular-mechanical (MM) calculations. The SMD simulations revealed interesting conformational changes of the protein. While no large-amplitude motions of the protein were observed during pore opening, the side chain rotation of the protonated external gating residue Glu148 was found to be critical for full access of the channel entrance by Cl–. Moving the anion into the external binding site (Sext) induced small-amplitude shifting of the protein backbone at the N-terminal end of helix F. As Cl– traveled through the pore, rigid-body swinging motions of helix R separated it from helix D. Helix R returned to its original position once Cl– exited the channel. Population analysis based on polarized wavefunction from QM/MM calculations discovered significant (up to 20%) charge loss for Cl– along the ion translocation pathway inside the pore. The delocalized charge was redistributed onto the pore residues, especially the functional groups containing π bonds (e.g., the Tyr445 side chain), while the charges of the H atoms coordinating Cl– changed almost negligibly. Potentials of mean force computed from umbrellamore » sampling at the QM/MM and MM levels both displayed barriers at the same locations near the pore entrance and exit. However, the QM/MM PMF showed higher barriers (~10 kcal/mol) than the MM PMF (~2 kcal/mol). Binding energy calculations indicated that the interactions between Cl– and certain pore residues were overestimated by the semi-empirical PM3 Hamiltonian and underestimated by the CHARMM36 force fields, both of which were employed in the umbrella sampling simulations. In particular, CHARMM36 underestimated binding interactions for the functional groups containing π bonds, missing the stabilizations of the Cl– ion due to electron delocalization. The results suggested that it is important to explore these quantum effects for accurate descriptions of the Cl– transport.« less

Authors:
 [1];  [1];  [1];  [1];  [1]
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  1. Univ. of Colorado, Denver, CO (United States). Dept. of Chemistry
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)
Sponsoring Org.:
USDOE
OSTI Identifier:
1524078
Resource Type:
Accepted Manuscript
Journal Name:
Frontiers in Chemistry
Additional Journal Information:
Journal Volume: 6; Journal ID: ISSN 2296-2646
Publisher:
Frontiers Research Foundation
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; QM/MM; CLC; chloride transport; electron delocalization; conformational change; umbrella sampling; steered molecular dynamics; potential of mean force

Citation Formats

Wang, Chun -Hung, Duster, Adam W., Aydintug, Baris O., Zarecki, MacKenzie G., and Lin, Hai. Chloride Ion Transport by the E. coli CLC Cl–/H+ Antiporter: A Combined Quantum-Mechanical and Molecular-Mechanical Study. United States: N. p., 2018. Web. doi:10.3389/fchem.2018.00062.
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Wang, Chun -Hung, Duster, Adam W., Aydintug, Baris O., Zarecki, MacKenzie G., & Lin, Hai. Chloride Ion Transport by the E. coli CLC Cl–/H+ Antiporter: A Combined Quantum-Mechanical and Molecular-Mechanical Study. United States. https://doi.org/10.3389/fchem.2018.00062
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Wang, Chun -Hung, Duster, Adam W., Aydintug, Baris O., Zarecki, MacKenzie G., and Lin, Hai. Tue . "Chloride Ion Transport by the E. coli CLC Cl–/H+ Antiporter: A Combined Quantum-Mechanical and Molecular-Mechanical Study". United States. https://doi.org/10.3389/fchem.2018.00062. https://www.osti.gov/servlets/purl/1524078.
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@article{osti_1524078,
title = {Chloride Ion Transport by the E. coli CLC Cl–/H+ Antiporter: A Combined Quantum-Mechanical and Molecular-Mechanical Study},
author = {Wang, Chun -Hung and Duster, Adam W. and Aydintug, Baris O. and Zarecki, MacKenzie G. and Lin, Hai},
abstractNote = {We performed steered molecular dynamics (SMD) and umbrella sampling simulations of Cl– ion migration through the transmembrane domain of a prototypical E. coli CLC Cl–/H+ antiporter by employing combined quantum-mechanical (QM) and molecular-mechanical (MM) calculations. The SMD simulations revealed interesting conformational changes of the protein. While no large-amplitude motions of the protein were observed during pore opening, the side chain rotation of the protonated external gating residue Glu148 was found to be critical for full access of the channel entrance by Cl–. Moving the anion into the external binding site (Sext) induced small-amplitude shifting of the protein backbone at the N-terminal end of helix F. As Cl– traveled through the pore, rigid-body swinging motions of helix R separated it from helix D. Helix R returned to its original position once Cl– exited the channel. Population analysis based on polarized wavefunction from QM/MM calculations discovered significant (up to 20%) charge loss for Cl– along the ion translocation pathway inside the pore. The delocalized charge was redistributed onto the pore residues, especially the functional groups containing π bonds (e.g., the Tyr445 side chain), while the charges of the H atoms coordinating Cl– changed almost negligibly. Potentials of mean force computed from umbrella sampling at the QM/MM and MM levels both displayed barriers at the same locations near the pore entrance and exit. However, the QM/MM PMF showed higher barriers (~10 kcal/mol) than the MM PMF (~2 kcal/mol). Binding energy calculations indicated that the interactions between Cl– and certain pore residues were overestimated by the semi-empirical PM3 Hamiltonian and underestimated by the CHARMM36 force fields, both of which were employed in the umbrella sampling simulations. In particular, CHARMM36 underestimated binding interactions for the functional groups containing π bonds, missing the stabilizations of the Cl– ion due to electron delocalization. The results suggested that it is important to explore these quantum effects for accurate descriptions of the Cl– transport.},
doi = {10.3389/fchem.2018.00062},
journal = {Frontiers in Chemistry},
number = ,
volume = 6,
place = {United States},
year = {Tue Mar 13 00:00:00 EDT 2018},
month = {Tue Mar 13 00:00:00 EDT 2018}
}
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https://doi.org/10.3389/fchem.2018.00062
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Figures / Tables:

FIGURE 1 FIGURE 1: Beginning geometry for steered molecular dynamics simulations, where the Cl− ion at the extracellular pore entrance (Cl1) was moved toward the intracellular side along the path indicated by the black dash curve and arrow. Approximate positions of the three binding sites Sext, Scen, and Sint were indicated bymore » the green circles. Also shown is another nearby Cl− ion (Cl2), which was attracted to Arg147 during the equilibration. The EcCLC antiporter transmembrane domain was illustrated in cartoon in yellow, with the helixes A–R labeled. Lipid molecules were depicted as lines (cyan, C; blue, N; red, O; and tan, P). For clarity, water molecules and ions are not displayed, except for the above two Cl− ion shown as green spheres.« less
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Selective Complexation of K + and Na + in Simple Polarizable Ion-Ligating Systems
journal, September 2010

  • Bostick, David L.; Brooks, Charles L.
  • Journal of the American Chemical Society, Vol. 132, Issue 38
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Discovery of CLC transport proteins: cloning, structure, function and pathophysiology: Discovery of CLC transport proteins
journal, August 2015

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Ab initio investigation of the atomic charges in the KcsA channel selectivity filter
journal, October 2004

Water access points and hydration pathways in CLC H + /Cl − transporters
journal, December 2013

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QM/MM: what have we learned, where are we, and where do we go from here?
journal, July 2006

Substrate-driven conformational changes in ClC-ec1 observed by fluorine NMR
journal, September 2009

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Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins
journal, July 2005

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Ion-binding properties of the ClC chloride selectivity filter
journal, December 2005

Multiscale Simulations Reveal Key Aspects of the Proton Transport Mechanism in the ClC-ec1 Antiporter
journal, March 2016

  • Lee, Sangyun; Swanson, Jessica M. J.; Voth, Gregory A.
  • Biophysical Journal, Vol. 110, Issue 6
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Intracellular Proton-Transfer Mutants in a CLC Cl − /H + Exchanger
journal, January 2009

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A provisional transport mechanism for a chloride channel-type Cl − /H + exchanger
journal, October 2008

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Optimization of parameters for semiempirical methods II. Applications
journal, March 1989

Charge Transfer and Polarization for Chloride Ions Bound in ClC Transport Proteins: Natural Bond Orbital and Energy Decomposition Analyses
journal, November 2013

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  • The Journal of Physical Chemistry B, Vol. 117, Issue 50
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Optimization of parameters for semiempirical methods I. Method
journal, March 1989

A pseudobond approach to combining quantum mechanical and molecular mechanical methods
journal, January 1999

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  • The Journal of Chemical Physics, Vol. 110, Issue 1
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Chloride ion conduction without water coordination in the pore of ClC protein
journal, January 2009

Natural population analysis
journal, July 1985

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  • The Journal of Chemical Physics, Vol. 83, Issue 2
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Gramicidin channel selectivity. Molecular mechanics calculations for formamidinium, guanidinium, and acetamidinium
journal, July 1992

Structure and gating of CLC channels and exchangers: Structure and gating of CLC channels and exchangers
journal, July 2015

  • Accardi, Alessio
  • The Journal of Physiology, Vol. 593, Issue 18
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Natural hybrid orbitals
journal, September 1980

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THE weighted histogram analysis method for free-energy calculations on biomolecules. I. The method
journal, October 1992

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Antiport Mechanism for Cl−/H+ in ClC-ec1 from Normal-Mode Analysis
journal, March 2010

  • Miloshevsky, Gennady V.; Hassanein, Ahmed; Jordan, Peter C.
  • Biophysical Journal, Vol. 98, Issue 6
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Charge delocalization upon chloride ion binding in ClC chloride ion channels/transporters
journal, January 2011

Separate Ion Pathways in a Cl − /H + Exchanger
journal, November 2005

  • Accardi, Alessio; Walden, Michael; Nguitragool, Wang
  • The Journal of General Physiology, Vol. 126, Issue 6
  • DOI: 10.1085/jgp.200509417

Conduction Mechanisms of Chloride Ions in ClC-Type Channels
journal, February 2004

The ClC family of chloride channels and transporters
journal, August 2006

Canonical dynamics: Equilibrium phase-space distributions
journal, March 1985

Molecular Dynamics Investigation of Cl− and Water Transport through a Eukaryotic CLC Transporter
journal, March 2012

Synergistic substrate binding determines the stoichiometry of transport of a prokaryotic H+/Cl− exchanger
journal, April 2012

  • Picollo, Alessandra; Xu, Yanyan; Johner, Niklaus
  • Nature Structural & Molecular Biology, Vol. 19, Issue 5
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A smooth particle mesh Ewald method
journal, November 1995

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Constant pressure molecular dynamics algorithms
journal, September 1994

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CLC channels and transporters: Proteins with borderline personalities
journal, August 2010

  • Accardi, Alessio; Picollo, Alessandra
  • Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1798, Issue 8
  • DOI: 10.1016/j.bbamem.2010.02.022

Exterior Site Occupancy Infers Chloride-Induced Proton Gating in a Prokaryotic Homolog of the ClC Chloride Channel
journal, September 2004

On the Non‐Orthogonality Problem Connected with the Use of Atomic Wave Functions in the Theory of Molecules and Crystals
journal, March 1950

  • Löwdin, Per‐Olov
  • The Journal of Chemical Physics, Vol. 18, Issue 3
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Ion permeation through a Cl--selective channel designed from a CLC Cl-/H+ exchanger
journal, August 2008

  • Jayaram, H.; Accardi, A.; Wu, F.
  • Proceedings of the National Academy of Sciences, Vol. 105, Issue 32
  • DOI: 10.1073/pnas.0804503105

Recent developments in QM/MM methods towards open-boundary multi-scale simulations
journal, May 2014

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