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

在这个由化学部的理论和计算化学计划以及分子和细胞生物科学部的分子生物物理学计划资助的奖项中，Steven Rick将从理论上研究水如何影响蛋白质与配体的结合和蛋白质的灵活性。将在三个方面开展工作。首先，用自由能微扰法计算连接配体和蛋白质的位置上加水分子的自由能，以考察水热力学和结合常数之间的关系。接下来，将通过模拟所有内部水分子和不使用所有内部水分子来测试内部水分子对蛋白质灵活性的影响。最后，我们将研究蛋白质空腔的简单模型中的水，这些空腔具有不同程度的亲水性。这项研究的一个关键部分是不同势的比较，包括极化模型。作为这项工作的一部分，瑞克将开发使用可极化势进行模拟的改进算法，以及用于大型系统的改进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。该项目的成果有望使人们更好地理解内部水分子对蛋白质灵活性的作用，并改进使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体系中结合水分子的热力学和结构的新认识。埋藏在蛋白质内部蛋白质和配体之间的水分子可以对生物分子的功能产生强烈的影响。例如，导致耐药性的突变被认为涉及到一个紧密结合的水分子的添加。里克将继续与新奥尔良南方大学(SUNO)合作，为SUNO的学生提供开展化学研究的机会。SUNO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.