Polarizable Mean-Field Model of Water for Biological Simulations with AMBER and CHARMM Force Fields

Abstract

Although a great number of computational models of water are available today, the majority of current biological simulations are done with simple models, such as TIP3P and SPC, developed almost thirty years ago and only slightly modified since then. The reason is that the non-polarizable force fields that are mostly used to describe proteins and other biological molecules are incompatible with more sophisticated modern polarizable models of water. The issue is electronic polarizability: in liquid state, in protein, and in vacuum the water molecule is polarized differently, and therefore has different properties; thus the only way to describe all these different media with the same model is to use a polarizable water model. However, to be compatible with the force field of the rest of the system, e.g. a protein, the latter should be polarizable as well. Here we describe a novel model of water that is in effect polarizable, and yet compatible with the standard non-polarizable force fields such as AMBER, CHARMM, GROMOS, OPLS, etc. Thus the model resolves the outstanding problem of incompatibility.

Thermodynamic Insight into the Effects of Water Displacement and Rearrangement upon Ligand Modifications using Molecular Dynamics Simulations

“…Regarding the representation of water molecules, it is questionable if simple models such as TIP3P or TIP4P,that were parametrized to reproduce properties of bulk water,yield accurate energies for structuralw aters, which can be expected to be polarized differently. [43] These shortcomings can explain why reachingc hemical accuracyw ith our presented estimation is not achievable for all cases;h owever,f or the two examples were the deviation between estimated and experimental change in binding free energy was 5kcal mol À1 or more, alternative explanations have to be considered. Insufficient sampling can be an important drawback.…”

Water models for biomolecular simulations

“…For example, experimentally observed change in the dipole moment of real water molecule upon transfer from gas to liquid phase is as large as 1D, while for a rigid fixed‐charge model that change is zero by construction. The polarity of micro‐environment near a macromolecule can be different from that of bulk water; the concern is that nonpolarizable models can not properly respond to different micro‐environments during the course of a simulation, e.g., enzymatic cleft versus bulk solvent or in crossmembrane transport.…”

“…This is one of the reasons that makes it difficult to test whether the higher physical realism offered by polarizable water models translates immediately into improved quality of biomolecular simulations—heavily parameterized fully polarizable gas‐phase force fields can mask improvements (or lack thereof) of new water models. However, a recent suggestion offers an elegant and computationally inexpensive procedure (one‐time re‐scaling of the partial charges) to restore consistency between a polarizable water model and a nonpolarizable gas‐phase force‐field, which may open the possibility of using polarizable water models with standard, nonpolarizable force‐fields.…”

Calcium Binding to Calmodulin by Molecular Dynamics with Effective Polarization

“…10,11 Recently, a computationally simple and physically welljustified scheme for including electronic polarization effects for ions in aqueous solutions and in interaction with proteins has been suggested. 12,13 The basic idea is to include electronic polarization in a mean-field way via rescaling the ionic charges by the inverse of the electronic part of water dielectric constant, that is, by a factor of 0.75. As a mean-field method, such an approach is applicable to homogeneous media in terms of electronic polarization.…”