Simulation of pH-Dependent Conformational Transitions in Membrane Proteins: The CLC-ec1 Cl-/H+ Antiporter. Academic Article uri icon

Overview

abstract

  • Intracellular transport of chloride by members of the CLC transporter family involves a coupled exchange between a Cl- anion and a proton (H+), which makes the transport function dependent on ambient pH. Transport activity peaks at pH 4.5 and stalls at neutral pH. However, a structure of the WT protein at acidic pH is not available, making it difficult to assess the global conformational rearrangements that support a pH-dependent gating mechanism. To enable modeling of the CLC-ec1 dimer at acidic pH, we have applied molecular dynamics simulations (MD) featuring a new force field modification scheme-termed an Equilibrium constant pH approach (ECpH). The ECpH method utilizes linear interpolation between the force field parameters of protonated and deprotonated states of titratable residues to achieve a representation of pH-dependence in a narrow range of physiological pH values. Simulations of the CLC-ec1 dimer at neutral and acidic pH comparing ECpH-MD to canonical MD, in which the pH-dependent protonation is represented by a binary scheme, substantiates the better agreement of the conformational changes and the final model with experimental data from NMR, cross-link and AFM studies, and reveals structural elements that support the gate-opening at pH 4.5, including the key glutamates Gluin and Gluex.

publication date

  • November 18, 2021

Research

keywords

  • Antiporters
  • Escherichia coli
  • Escherichia coli Proteins

Identity

PubMed Central ID

  • PMC8625536

Scopus Document Identifier

  • 85120681788

Digital Object Identifier (DOI)

  • 10.1016/0167-4838(88)90152-5

PubMed ID

  • 34834047

Additional Document Info

volume

  • 26

issue

  • 22