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

水对蛋白质-配体结合和蛋白质灵活性的贡献

• 批准号: 0611679
• 负责人: Steven Rick
• 金额: $ 34.26万
• 依托单位: University of New Orleans
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0611679&HistoricalAwards=false
• 关键词: Contribution; Water; Protein; Ligand; Binding

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.

在这个由化学部理论和计算化学项目以及分子和细胞生物科学部分子生物物理学项目资助的奖项中，史蒂文·里克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，将使用自由能扰动计算将水分子添加到桥接配体和蛋白质的位置的自由能，以检查水热力学和结合常数之间的相关性。接下来，将通过有和没有所有内部水分子的模拟来测试内部水分子对蛋白质柔性的影响。最后，将检查蛋白质空腔简单模型中的水，其中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比较不同的潜力，包括极化模型。作为这项工作的一部分，Rick 将开发改进的算法，用于使用可极化电位实施模拟，以及改进大型系统的副本交换采样方法。这些进展将通过 CHARMM 计划向科学界公开。该项目的成果预计将有助于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进行蛋白质模拟的方法。这项研究的结果将带来关于生物系统中结合水分子的热力学和结构的新知识。埋藏在蛋白质和配体之间的蛋白质内部的水分子可以对生物分子的功能产生强烈影响。 例如，导致耐药性的突变被认为涉及添加紧密结合的水分子。 Rick 将继续与新奥尔良南方大学 (SUNO) 合作，该大学历史上是一所黑人为主的本科院校，为 SUNO 学生提供开展化学研究的机会。