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，这项研究得到了分子和细胞生物科学部的分子生物物理计划和化学部的理论和计算计划的资助。为了实现这一点，Ichiye博士正在为生物大分子的计算机模拟开发快速而准确的溶剂处理方法。本项目致力于水的软粘性偶极(SSD)势能模型的发展。单点SSD模型比通常用于生物模拟的三点模型有很大的进步，因为它具有更好的结构、介电和动力学性质，而且在分子动力学模拟中的速度是三点模型的四倍。SSD模型将水分子表示为Lennard-Jones球体、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。科学目标是(1)确定Rubredosin和其他铁-硫蛋白质内部和周围的水的特征，特别是在金属位置附近，以及(2)在水密度的温度依赖性和过冷水的动力学中确定异常的物理来源。由于这些问题需要很长的模拟时间，并且可能在很大程度上取决于氢键势，因此SSD是这些研究的理想选择。SSD模型的发展将影响许多领域的研究。对于整个科学界来说，开发用于计算机模拟的快速而准确的水模型对于理解水的复杂行为以及极大地提高涉及水溶液中的溶质(包括生物大分子)的模拟的速度和精度是非常重要的。在这项研究中，准确表征铁硫蛋白金属中心附近的水的结构和动力学是至关重要的，因为它强烈地影响着它们的电子转移性质。具体地说，计算机模拟将被用来研究通过“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专一性的机制。

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.