The Role of Electrostatics in Enzymes: Do Biomolecular Force Fields Reflect Protein Electric Fields?

Abstract

<div><div><div><p>Preorganization of large, directionally oriented, electric fields inside protein active sites has been proposed as a crucial contributor to catalytic mechanism in many enzymes, and may be efficiently investigated at the atomistic level with molecular dynamics simulations. Here we evaluate the ability of the AMOEBA polarizable force field, as well as the additive Amber ff14SB and Charmm C36m models, to describe the electric fields present inside the active site of the peptidyl-prolyl isomerase cyclophilin A. We compare the molecular mechanical electric fields to those calculated with a fully first principles quantum mechanical (QM) representation of the protein, solvent, and ions, and find that AMOEBA consistently shows far greater correlation with the QM electric fields than either of the additive force fields tested. Catalytically-relevant fields calculated with AMOEBA were typically smaller than those observed with additive potentials, but were generally consistent with an electrostatically-driven mechanism for catalysis. Our results highlight the accuracy and the potential advantages of using polarizable force fields in systems where accurate electrostatics may be crucial for providing mechanistic insights.</p></div></div></div>

Water Nanoconfined in a Hydrophobic Pore: Molecular Dynamics Simulations of Transmembrane Protein 175 and the Influence of Water Models

“…31,32 Thus, recent studies have explored the influence of polarizable models on, for example, simulations of the interactions of ions with lipid bilayer membranes, 33 simple model ion channels, 34 and on electric field strength within the active site of an enzyme. 35 The effect of polarizable water models within synthetic nanoconfined environments under an electric field has also been investigated, with the conclusion that polarizability can affect the structure and dynamics of the systems. 36−38 Various rigid fixed-charge water models have also been assessed for ligand binding in host/guest systems 39 and for water behavior in peptide nanotubes.…”

Heme Hopping Falls Short: What Explains Anti-Arrhenius Conductivity in a Multi-heme Cytochrome Nanowire?

“…C(E,pH)MD simulations captured much of the same behavior for E ° along the heme chain as QM/MM@MD, except that (1) the swings in E ° were more accentuated, as is expected for a fix-point charge electrostatics method, 114 and (2) the E ° of #6 was more, not less negative than #5 . The latter discrepancy may reflect the difficulty of assigning dielectric boundaries for the implicit solvent used in electrostatic free energy evaluations at the interface of subunits in the filament where #6 resided.…”

Induced Polarization in Molecular Dynamics Simulations of the 5-HT3 Receptor Channel

“…Furthermore, the AMOEBA polarizable force field has recently been shown to yield a more accurate estimate of the electric field within the active site of an enzyme, as shown by correlation with quantum mechanically calculated electric fields compared to additive models. 33 Considering the potential of such polarizable force fields to more accurately predict the behavior of water, we therefore decided to quantify the effects of induced polarization experienced by water within an ion channel and its impact on the predicted hydration equilibrium of such pores. In this study, we describe protocols for polarizable MD simulation of membrane protein (ion channel) systems and compare the pore hydration behavior of polarizable water models to that of fixed point-charge models.…”