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，该研究由分子和细胞生物科学部的分子生物物理学计划以及化学部的理论和计算计划资助。 为了实现这一目标，Ichiye博士正在开发快速准确的溶剂处理方法，用于生物大分子的计算机模拟。 该项目的重点是开发水的软粘性偶极子（SSD）势能模型。 单站点SSD模型是一个相当大的进步，通常用于生物模拟的三个站点的模型，因为它具有更好的结构，介电和动力学特性，但在分子动力学模拟的速度是四倍。 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，在SSD模型中，两个水分子之间的相互作用能仅取决于每个分子的位置和取向，而在三位模型中，它取决于每个分子的氧和两个氢的位置。 发展该模型的目的是（1）进一步研究其纯水性质，（2）改善水-溶质相互作用，（3）将其实现为生物大分子的分子力学计算机程序，（4）增加电子极化率。 科学目的是（1）表征红氧还蛋白和其他铁硫蛋白中及其周围的水，特别是金属位点附近的水，以及（2）确定水密度与温度的依赖性和过冷水动力学异常的物理起源。 由于这些问题需要很长的模拟时间，并可能在很大程度上取决于氢键势，SSD是这些研究的理想选择。SSD模型的发展将影响许多研究领域。 对于整个科学界来说，开发快速但准确的水模型用于计算机模拟对于理解水的复杂行为以及大大提高水溶液中溶质（包括生物大分子）模拟的速度和准确性非常重要。 在这项研究中，铁硫蛋白金属位点附近水的结构和动力学的准确表征是至关重要的，因为它强烈影响它们的电子转移特性。 具体来说，计算机模拟将被用来调查是否水进入蛋白质通过“水门”作为一种机制，控制这些蛋白质中的电子转移特异性。

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.