Influence of electronic polarization in a chloride-pumping rhodopsin binding site
Biophysical Journal Elsevier 122:3 (2023) 112a-113a
Electronic Polarizability Tunes the Function of the Human Bestrophin 1 Cl−Channel
(2023)
Abstract:
Mechanisms of anion permeation within ion channels and nanopores remain poorly understood. Recent cryo-electron microscopy structures of the human bestrophin 1 chloride channel (hBest1) provide an opportunity to evaluate ion interactions predicted by molecular dynamics (MD) simulations against experimental observations. We implement the fully polarizable forcefield AMOEBA in MD simulations of open and partially-open states of the hBest1. The AMOEBA forcefield models multipole moments up to the quadrupole; therefore, it captures induced dipole and anion- π interactions. By including polarization we demonstrate the key role that aromatic residues play in ion permeation and the functional advantages of pore asymmetry within the highly conserved hydrophobic neck of the pore. We establish that these only arise when electronic polarization is included in the molecular models. We also show that Cl − permeation in this region can be achieved through hydrophobic solvation concomitant with partial ion dehydration, which is compensated for by the formation of contacts with the edge of the phenylalanine ring. Furthermore, we demonstrate how polarizable simulations can help determine the identity of ion-like densities within high-resolution cryo-EM structures. Crucially, neglecting polarization in simulation of these systems results in the localization of Cl − at positions that do not correspond with their experimentally resolved location. Overall, our results demonstrate the importance of including electronic polarization in realistic and physically accurate models of biological systems.Statement of Significance
Ion channels are nanoscale protein pores that enable the selective passage of charged ions across cell membranes. Understanding the underlying mechanisms for selective anion permeation through such pores remains a challenge. To simulate their behavior efficiently in silico , fixed charge models are typically employed. However, this approach is insufficient for the study of anions. Here, we use simulations with explicit treatment of electrostatics to investigate the interactions of chloride ions in the human bestrophin 1 channel. We find that electronic polarization tunes the state of the channel and affects the interactions of chloride ions thereby revealing a mechanism for permeation. Furthermore, these simulations can be used to resolve experimental ambiguity in ion-like densities from cryo-EM structures.Influence of Electronic Polarization on the Binding of Anions to a Chloride-Pumping Rhodopsin
(2023)
When is a hydrophobic gate not a hydrophobic gate?
The Journal of general physiology 154:11 (2022) e202213210
Abstract:
The flux of ions through a channel is most commonly regulated by changes that result in steric occlusion of its pore. However, ion permeation can also be prevented by formation of a desolvation barrier created by hydrophobic residues that line the pore. As a result of relatively minor structural changes, confined hydrophobic regions in channels may undergo transitions between wet and dry states to gate the pore closed without physical constriction of the permeation pathway. This concept is referred to as hydrophobic gating, and many examples of this process have been demonstrated. However, the term is also now being used in a much broader context that often deviates from its original meaning. In this Viewpoint, we explore the formal definition of a hydrophobic gate, discuss examples of this process compared with other gating mechanisms that simply exploit hydrophobic residues and/or lipids in steric closure of the pore, and describe the best practice for identification of a hydrophobic gate.Gain-of-function mutations in KCNK3 cause a developmental disorder with sleep apnea
Nature Genetics Nature Research 54:10 (2022) 1534-1543