Modeling the Role of Water in Protein Structure and Function

Abstract

Water is a solvent with high static dielectric constant, substantial dipole moment, significant electronic polarizability, and a dynamic hydrogen-bonding network. As such, water plays a pivotal role in protein structure and function, the molecular mechanisms of which remain challenging to determine. This dissertation develops and applies computational frameworks to rigorously integrate water effects on protein structure and function. We first examine how stronger protein–water interactions in the classical AMOEBA force field produce more realistic deformation behavior in collagen mimetic peptides (CMPs). In particular, our simulations of (PPG)$_n$ CMPs ($n=5,12,25$) under physiological conditions capture the experimental observation that shorter CMPs deform more strongly than longer ones. To better characterize these CMPs, we developed textsc{HeliXplore}, an open-source Python package for analyzing single- and multi-strand deformations. We further report that the length-dependent deformation we observe is associated with anisotropic translational and rotational relaxation dynamics of surrounding water molecules. Overall, we show that AMOEBA offers a substantial improvement over traditional force fields that often underestimate protein–water interactions. We next investigate the diffusion of solvated sodium ions through voltage-gated sodium channels (Na$_{mathrm{v}}$s). To do so, we develop a Continuous-Time Random Walk (CTRW) model that describes microscopic diffusion as a function of spatial and temporal disorder at the molecular scale. In addition, we establish a framework that incorporates this molecular disorder using information from polarizable MD simulations, enabling a consistent bottom-up approach. Using the CTRW model, we show that increased temporal disorder of the ion can accelerate diffusion in disordered media. More broadly, our results suggest that structural dynamics may help explain how Na${_mathrm{v}}$s achieve both high selectivity, through strong sodium binding, and rapid ion diffusion across the membrane.