OPC3/LEW: A New Flexible Three-Site Water Model to Simulate Low-Electrostatic Environments

Abstract

One of the main goals of computational simulations is to closely reproduce the environmental conditions in which biomolecules perform their physiological functions. However, the choice of water model is often based more on computational cost than on its effect on the molecular environment, as is the case with membrane proteins. These systems fulfill their biological function in low-polarity molecular environments that the most common or currently available water models do not reproduce accurately. In this work, we present a new flexible water model with three interaction sites that accurately represents the low-polarity electrostatic environment typically observed in the proximity of membrane systems. Using molecular dynamics simulations and based on the interaction parameters of OPC3, this new low-electrostatic water model (OPC3/LEW) reproduces dielectric constants close to 20. Following the methodology of Aguilar-Pineda et al. for developing low-electrostatic models by opening the H–O–H angle, the bulk density and surface tension of blood plasma under physiological conditions were selected as target properties. The performance of the OPC3/LEW model was validated by evaluating nine thermodynamic properties as a pure component and its ability to preserve helical structures as a solvating medium for eight amphipathic peptides. Outcomes were compared with those obtained using four water models with three interaction sites: OPC3, OPC3-B, SPC/E, and TIP3P. Findings show that the OPC3/LEW model reproduces several properties of bulk water more accurately than models such as SPC/E and TIP3P at the evaluated temperatures. However, its greatest strength lies in preserving the helical structures of peptides that otherwise would adopt disordered states. Although its main limitation is the geometry of its open structure, which makes the model somewhat unrealistic, the findings suggest that the OPC3/LEW model could be used in systems involving low-polarity environments, such as membrane proteins.