Structure and Dynamics of the Solvation of Bovine Pancreatic Trypsin Inhibitor in Explicit Water:  A Comparative Study of the Effects of Solvent and Protein Polarizability

Abstract

To isolate the effects of the inclusion of polarizability in the force field model on the structure and dynamics of the solvating water in differing electrostatic environments of proteins, we present the results of molecular dynamics simulations of the bovine pancreatic trypsin inhibitor (BPTI) in water with force fields that explicitly include polarization for both the protein and the water. We use three model potentials for water and two model potentials for the protein. Two of the water models and one of the protein models are polarizable. A total of six systems were simulated representing all combinations of these polarizable and nonpolarizable protein and water force fields. We find that all six systems behave in a similar manner in regions of the protein that are weakly electrostatic (either hydrophobic or weakly hydrophilic). However, in the vicinity of regions of the protein with relatively strong electrostatic fields (near positively or negatively charged residues), we observe that the water structure and dynamics are dependent on both the model of the protein and the model of the water. We find that a large part of the dynamical dependence can be described by small changes in the local environments of each region that limit the local density of non-hydrogen-bonded waters, precisely the water molecules that facilitate the dynamical relaxation of the water-water hydrogen bonds. We introduce a simple method for rescaling for this effect. When this is done, we are able to effectively isolate the influence of polarizability on the dynamics. We find that the solvating water's relaxation is most affected when both the protein and the water models are polarizable. However, when only one model (or neither) is polarizable, the relaxation is similar regardless of the models used.

A Single Mutation in a Tunnel to the Active Site Changes the Mechanism and Kinetics of Product Release in Haloalkane Dehalogenase LinB

“…The nonpolarizable model will also affect the interactions of the ion with polarizable protein side chains, such as the halide-stabilizing residues Asn-38 and Trp-109, which in turn may be underestimated (53). Moreover, the explicit water models used in the simulations were developed to describe the bulk solvent behavior and the balance of water-water and protein-water interactions, but they may not be accurate in describing the properties of buried water molecules in protein cavities (54), especially in the presence of charged groups (55). Nevertheless, our results show that these imprecisions cancel out if we focus on the relative differences between the two studied systems, possibly due to the relatively small perturbation of the system caused by the mutation.…”

The large quadrupole of water molecules

“…Moreover, although great progress has been made using nonpolarizable models for systems involving hydrophilic versus hydrophobic environments such as the free energies of transfer between water and organic phases, 44 polarizability has been shown to be important for water near charged residues in proteins 45 so that further investigations of adding polarizability to multipole models are also warranted. For instance, an approach for Ewald summation of multipole interactions including polarizability up to the quadrupolar level has been presented by Aguado and Madden, 46 which could be extended to higher multipoles.…”

Efficient Simulation Method for Polarizable Protein Force Fields: Application to the Simulation of BPTI in Liquid Water

“…In a following study 66 we will be interested in studying the dynamic properties of water solvent in the vicinity of the protein. To ensure an accurate evaluation of these properties our simulations are conducted at constant energy and constant volume free of artificial perturbations necessary to simulate in the isothermal/isobaric ensemble.…”