Theoretical Studies of Aqueous Solvation of Proteins

Georgetown University, Washington DC

Investigators

Abstract

This project will lead to a better understanding of the physical origins of protein-water interactions and also the anomalous properties of liquid water. Water plays a crucial role in the structure and function of proteins such as in folding, enzymatic activity, and molecular recognition. However, water is a complex solvent whose properties are still not completely understood. The overall goals of this project are 1) to develop fast and accurate treatments of solvent effects in computer simulations of biological macromolecules and 2) to understand the nature of protein solvation using computer simulations. The focus of this project is on the development of the new soft, sticky dipole-quadrupole-octopole (SSDQO) potential energy model of water for computer simulations of biological systems. The SSDQO model is a modification of the old soft, sticky dipole (SSD) single-point model, which was an advance over the three-site models commonly used for biological simulations because it has better structural, dielectric and dynamical properties and yet is four times faster in molecular dynamics (MD) and seven times faster in Monte Carlo (MC) simulations. The new SSDQO model is a single-point model with a Lennard-Jones sphere and a point dipole, quadrupole, and octopole and the new sticky interaction potential is an approximate moment expansion. The first objective is to optimize the moment parameters of the SSDQO model to reproduce the properties of liquid water. Thermodynamic, dynamic and structural properties will be calculated using MD and/or MC simulations and compared with experimental data. Once the non-polarizable model is optimized, polarization will be added consistent with the CHARMM force field. Second objective is to elucidate the underlying physics of protein-water interactions. First, the solvation of simple peptides in SSDQO water will be studied by MD and/or MC simulations and compared with experimental data. Next, rubredoxin in solution and crystalline environment using SSDQO water will be studied using MD simulations and compared to simulations using TIP3P water and a high-resolution crystal structure. Third objective is to determine the physical origins of the anomalous properties of liquid water, which is also important for validating the use of the model under a wide range of conditions such as in a crowded living cell. The temperature dependence of the density and of the diffusion constant of SSDQO water will be studied in MD simulations using the decomposition of the energy into moment terms in the SSDQO potential. Fourth objective is to extend the SSDQO model to complicated molecules such as proteins, which represents a future direction for this research. The feasibility of extending the approximate moment expansion to other molecules and chemical moieties such as peptides within molecules will be examined via MC simulations. This project will lead to increased speed and accuracy of computer simulations of a wide variety of biological, chemical and physical systems involving liquid water. The model will be made compatible with the CHARMM force field and will be implemented into the CHARMM computer program, which is widely used for molecular mechanics/dynamics studies of biomolecules. Thus, the model will be readily accessible to other researchers. This research will also train students in computational science. The principal investigator's group is ethnically and racially diverse and currently has two female graduate students. Outreach efforts will focus on women, who are traditionally underrepresented in mathematical and computational areas of science.