Theoretical Studies of Aqueous Solvation of Proteins

这项研究的长期目标是了解水对蛋白质结构和功能的影响，该研究由分子与细胞生物科学部的分子生物物理项目和化学部的理论与计算项目资助。为了实现这一目标，一野博士正在为生物大分子的计算机模拟开发快速准确的溶剂处理方法。本项目重点发展水的软粘偶极子（SSD）势能模型。单位点固态硬盘模型相对于生物模拟中常用的三位点模型有很大的进步，因为它具有更好的结构、介电性和动力学特性，而且在分子动力学模拟中速度快4倍。SSD模型将水分子表示为Lennard-Jones球、点偶极子和四面体“粘性”氢键势。因此，两个水分子之间的相互作用能在固态水模型中仅取决于每个分子的位置和取向，而在三位点模型中则取决于每个分子中氧和两个氢的位置。开发该模型的目的是：(1)进一步研究其纯水性质，(2)改善水-溶质相互作用，(3)将其应用于生物大分子的分子力学计算机程序中，(4)增加电子极化率。科学目标是(1)表征红氧还蛋白和其他铁硫蛋白内部和周围的水，特别是在金属位点附近；(2)确定水密度的温度依赖性和过冷水动力学中的异常的物理起源。由于这些问题需要很长的模拟时间，并且可能主要取决于氢键势，因此SSD是这些研究的理想选择。固态硬盘模型的发展将影响许多研究领域。对于整个科学界来说，开发快速而准确的水计算机模拟模型对于理解水的复杂行为以及大大提高溶质（包括生物大分子）在水溶液中的模拟速度和准确性非常重要。在本研究中，准确表征铁硫蛋白金属位点附近的水的结构和动力学是至关重要的，因为它强烈影响它们的电子转移性质。具体而言，计算机模拟将用于研究通过“水门”进入蛋白质的水是否作为控制这些蛋白质中电子转移特异性的机制。

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.