The functional properties of some biological ion channels and membrane transport proteins are proposed to exploit anion-hydrophobic interactions. Here, we investigate a chloride-pumping rhodopsin as an example of a membrane protein known to contain a defined anion binding site composed predominantly of hydrophobic residues. Using molecular dynamics simulations, we explore Cl- binding to this hydrophobic site and compare the dynamics arising when electronic polarization is neglected (CHARMM36 [c36] fixed-charge force field), included implicitly (via the prosECCo force field), or included explicitly (through the polarizable force field, AMOEBA). Free energy landscapes of Cl- moving out of the binding site and into bulk solution demonstrate that the inclusion of polarization results in stronger ion binding and a second metastable binding site in chloride-pumping rhodopsin. Simulations focused on this hydrophobic binding site also indicate longer binding durations and closer ion proximity when polarization is included. Furthermore, simulations reveal that Cl- within this binding site interacts with an adjacent loop to facilitate rebinding events that are not observed when polarization is neglected. These results demonstrate how the inclusion of polarization can influence the behavior of anions within protein binding sites and can yield results comparable with more accurate and computationally demanding methods.

Clarendon Laboratory Department of Physics University of Oxford Oxford UK; Department of Biochemistry University of Oxford Oxford UK

Clarendon Laboratory Department of Physics University of Oxford Oxford UK; Kavli Institute for Nanoscience Discovery University of Oxford Oxford UK

Department of Biochemistry University of Oxford Oxford UK

Department of Biochemistry University of Oxford Oxford UK; IBM Research Europe Hartree Centre Daresbury UK

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Prague 6 Czech Republic

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