Influence of electronic polarization on the binding of anions to a chloride-pumping rhodopsin

Phan, Linda X.; Chamorro, Victor Cruces; Martinez‐Seara, Hector; Crain, Jason; Sansom, Mark S.P.; Tucker, Stephen J.

doi:10.1016/j.bpj.2023.03.026

Cited by 4 publications

(4 citation statements)

References 41 publications

(66 reference statements)

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“…Various novel and important reports of weak interactions continue to emerge. For example, phosphorothioate DNA backbone (e.g., sulfur replacement of one phosphate oxygen atom) facilitates the interaction of even non‐DNA binding proteins with DNA through the weak interactions of the sulfur anion with alkyl groups of Lys/Arg residues (Hyjek‐Skladanowska et al, 2023), electronic polarization facilitates the interaction of the chloride anion with aliphatic protons in chloride‐pumping rhodopsin (Phan et al, 2023), or aromatic quadrupole in heme pockets modulates gas (e.g., NO, CO) binding (Adams et al, 2023). As the appreciation of weak interactions (of anions) in proteins continues to grow, we utilized AQcalc to generate an analysis of AQ (and CP, SB, and HBAQ) interactions in a variety of protein structures.…”

Section: Discussionmentioning

confidence: 99%

AQcalc: A web server that identifies weak molecular interactions in protein structures

Afshinpour,

Smith,

Chakravarty

2023

Protein Science

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Weak molecular interactions play an important role in protein structure and function. Computational tools that identify weak molecular interactions are, therefore, valuable for the study of proteins. Here, we present AQcalc, a web server (https://aqcalcbiocomputing.com/) that can be used to identify anion–quadrupole (AQ) interactions, which are weak interactions involving aromatic residue (Trp, Tyr, and Phe) ring edges and anions (Asp, Glu, and phosphate ion) both within proteins and at their interfaces (protein‐protein, protein‐nucleic acids, and protein‐lipid bilayer). AQcalc identifies AQ interactions as well as clusters involving AQ, cation–π, and salt bridges, among others. Utilizing AQcalc we analyzed weak interactions in protein models, even in the absence of experimental structures, to understand the contributions of weak interactions to deleterious structural changes, including those associated with oncogenic and germline disease variants. We identified several deleterious variants with disrupted AQ interactions (comparable in frequency to cation–π disruptions). Amyloid fibrils utilize AQ to bury anions at frequencies that far exceed those observed for globular proteins. AQ interactions were detected three and five times more frequently than the hydrogen‐bonded AQ (HBAQ) in fibril structures and protein‐lipid bilayer interfaces, respectively. By contrast, AQ and HBAQ interactions were detected with similar frequencies in globular proteins. Collectively, these findings suggest AQcalc will be effective in facilitating fine structural analysis. As other web utilities designed to identify protein residue interaction networks do not report AQ interactions, wide use of AQcalc will enrich our understanding of residue interaction networks and facilitate hypothesis testing by identifying and experimentally characterizing these comparably weak but important interactions.This article is protected by copyright. All rights reserved.

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Section: Discussionmentioning

confidence: 99%

AQcalc: A web server that identifies weak molecular interactions in protein structures

Afshinpour,

Smith,

Chakravarty

2023

Protein Science

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“…Therefore, one should expect more reasonable di↵erences and selectivities when comparing halides in biological systems. 50 4 Discussion and Conclusions…”

Section: Ecc Ions Are Required For Biomolecular Simulations Using Pro...mentioning

confidence: 98%

Effective Inclusion of Electronic Polarization Improves the Description of Electrostatic Interactions: The prosECCo75 Biomolecular Force Field

Nencini,

Tempra,

Biriukov

et al. 2024

Preprint

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prosECCo75 is an optimized force field effectively incorporating electronic polarization via charge scaling. It aims to enhance the accuracy of nominally nonpolarizable molecular dynamics (MD) simulations for interactions in biologically relevant systems involving water, ions, proteins, lipids, and saccharides. Recognizing the inherent limitations of nonpolarizable force fields in precisely modeling electrostatic interactions essential for various biological processes, we mitigate these shortcomings by accounting for electronic polarizability in a physical rigorous mean-field way that does not add to computational costs. With this scaling of (both integer and partial) charges within the CHARMM36 framework, prosECCo75 addresses overbinding artifacts. This improves agreement with experimental ion binding data across a broad spectrum of systems - lipid membranes, proteins (including peptides and amino acids), and saccharides - without compromising their biomolecular structures. prosECCo75 thus emerges as a computationally efficient tool providing enhanced accuracy and broader applicability in simulating the complex interplay of interactions between ions and biomolecules, pivotal for improving our understanding of many biological processes.

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“…Mutagenesis studies of the cBest1 neck residues to alanine later showed no effect on ion selectivity and suggested that the role of anion- π interactions may reduce the energy barriers for Cl − and other anions to permeate the neck region but not be the determining factor for charge selectivity (42, 43). Other forms of hydrophobic solvation mechanisms have previously been observed in simulations of a biomimetic nanopore (44) and a hydrophobic protein binding site (32) whereby Cl − moved through pores by partially dehydrating and forming energetically favorable interactions with hydrophobic contacts.…”

Section: Introductionmentioning

confidence: 96%

“…S1 ). Previous studies of reduced systems of ion channels focusing on isolated sections have shown that they can provide an accurate representation of the dynamics within the original protein (6, 31, 32). To validate the protein fragment, we performed simulations of the full protein embedded in a lipid bilayer compared with the protein fragment and analyzed the average water density.…”

Section: Introductionmentioning

confidence: 99%

Electronic Polarizability Tunes the Function of the Human Bestrophin 1 Cl⁻ Channel

Phan,

Owji,

Yang

et al. 2023

Preprint

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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-πinteractions. 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 SignificanceIon 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 efficientlyin 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.

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Influence of electronic polarization on the binding of anions to a chloride-pumping rhodopsin

Cited by 4 publications

References 41 publications

AQcalc: A web server that identifies weak molecular interactions in protein structures

AQcalc: A web server that identifies weak molecular interactions in protein structures

Effective Inclusion of Electronic Polarization Improves the Description of Electrostatic Interactions: The prosECCo75 Biomolecular Force Field

Electronic Polarizability Tunes the Function of the Human Bestrophin 1 Cl⁻ Channel

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