The Contribution of Water to Protein-Ligand Binding and Protein Flexibility

该奖项由化学部门的理论和计算化学项目以及分子和细胞生物科学部的分子生物物理学项目资助，Steven Rick将从理论上研究水如何影响蛋白质-配体结合和蛋白质灵活性。将在三个领域开展工作。首先，将一个水分子添加到配体和蛋白质的桥接位置上的自由能将使用自由能摄动来计算，以便检查水热力学和结合常数之间的相关性。接下来，将测试内部水分子对蛋白质柔韧性的影响，通过模拟有和没有所有内部水分子。最后，水在蛋白质空腔的简单模型将被检查，这些空腔有不同程度的亲水性。本研究的一个关键部分是比较不同的电位，包括极化模型。作为工作的一部分，Rick将开发改进的算法来实现使用极化电位的模拟，以及改进的大型系统的副本交换采样方法。这些进展将通过CHARMM计划提供给科学界。本项目的结果有望更好地理解内部水分子对蛋白质柔韧性的作用，并改进用显式溶剂模拟蛋白质的方法。这项研究的结果将导致对生物系统中结合水分子的热力学和结构的新认识。埋在蛋白质内部蛋白质和配体之间的水分子对生物分子的功能有很强的影响。例如，导致耐药性的突变被认为与一个紧密结合的水分子的添加有关。里克将继续与新奥尔良南方大学（SUNO）合作，为SUNO的学生提供进行化学研究的机会，这是一所历史上以黑人为主的本科院校。

In this award funded by the Theoretical and Computational Chemistry Program of the Chemistry Division and the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences, Steven Rick will examine theoretically how water affects protein-ligand binding and protein flexibility. Work will be pursued in three areas. First, the free energy of adding a water molecule to positions bridging a ligand and a protein will be calculated using free energy perturbation, in order to examine the correlation between water thermodynamics and binding constants. Next, the influence of interior water molecules on protein flexibility will be tested, by simulations both with and without all interior water molecules. Finally, water in simple models for protein cavities will be examined, where these cavities have varying degrees of hydrophilicity. A key part of this research is the comparison of different potentials, including polarizable models. As part of the effort, Rick will develop improved algorithms for implementing simulations using polarizable potentials as well as improved replica exchange sampling methods for large systems. These developments will be made available to the scientific community through the CHARMM program. Outcomes of this project are expected to lead to better understanding of the role of interior water molecules on protein flexibility, and improved methods for protein simulations with explicit solvent. The results of this research will lead to new knowledge of the thermodynamics and structure of bound water molecules in biological systems. Water molecules that are buried in protein interiors between a protein and a ligand can have strong influences on function of biomolecules. For example, the mutations that lead to drug resistance are thought to involve the addition of a tightly bound water molecule. Rick will continue his association with Southern University of New Orleans (SUNO), a historically black primarily undergraduate institution, to offer SUNO students opportunities to carry out research in chemistry.