Theoretical Studies of Aqueous Solvation of Proteins

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The long-term goal of this research, funded by the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences and the Theoretical and Computational Program in the Division of Chemistry, is to understand the influence of water on the structure and function of proteins. To accomplish this, Dr. Ichiye is developing fast and accurate treatments of solvent for computer simulations of biological macromolecules. This project focuses on the development of the soft, sticky dipole (SSD) potential energy model of water. The single-site SSD model is a considerable advance over three-site models commonly used for biological simulations because it has better structural, dielectrical and dynamical properties and yet is four times faster in molecular dynamics simulations. The SSD model represents a water molecule as a Lennard-Jones sphere, a point dipole, and a tetrahedral "sticky" hydrogen bond potential. Therefore, the interaction energy between two water molecules depends only on the position and orientation of each molecule in the SSD model, whereas it depend on the positions of the oxygen and the two hydrogens of each molecule in the three-site models. The aims in developing the model are (1) to investigate its pure water properties further, (2) to improve the water-solute interaction, (3) to implement it into a molecular mechanics computer program for biological macromolecules, and (4) to add electronic polarizability. The scientific aims are (1) to characterize water in and around rubredoxin and other iron-sulfur proteins, particularly near the metal site, and (2) to determine the physical origins of the anomalies in the temperature-dependence of water density and in the dynamics of supercooled water. Since these issues require very long simulation times and may depend crucially on the hydrogen bond potential, SSD is ideal for these studies.The development of the SSD model will impact many areas of research. For the scientific community as a whole, the development of fast but accurate models of water for computer simulations is important for understanding the complex behavior of water as well as for greatly improving the speed and accuracy of simulations involving solutes (including biological macromolecules) in aqueous solution. In this research, the accurate characterization of the structure and dynamics of water near the metal sites of iron-sulfur proteins is crucial because it strongly affects their electron transfer properties. Specifically, computer simulations will be used to investigate whether water entering the protein via "water gates" serves as a mechanism for controlling electron transfer specificity in these proteins.