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Exploiting Water Network Perturbations in Protein Binding Sites

利用蛋白质结合位点的水网络扰动

基本信息

批准号：
10621368
负责人：
Marcus Fischer
金额：
$ 44.86万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-05-31
项目状态：
未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Water enables life. So much so that the search for extraterrestrial life is a search for liquid water. However, terrestrial drug discovery still, by and large, ignores water molecules. The reason lies in the complexity and versatility of its contributions to biomolecular interactions, despite its apparent simplicity. My prior research has investigated the role of water in ligand recognition and selectivity, and its utility to improve ligand discovery. Recently, my lab has established a link between the mobility of water networks and the affinity of ligand binding to proteins. More generally, the work highlights the exploitable sensitivity of water networks in response to changes in protein and ligand. My long-term goal is to link atomic-scale water wiggles to changes in the protein conformational landscape and ultimately to organismal fitness. To achieve this, I aspire to pave the path to a more dynamic view of protein function that integrates currently neglected aspects of protein flexibility and hydration. This is important because cryogenic structures, which make up 95% of the Protein Data Bank, deliver a contorted, static image which is then used to design ligands. The objective of the proposed work is to formulate a pragmatic framework that defines and utilizes water network dynamics. As water is ubiquitously found at all biological interfaces, the concept extends beyond protein-ligand interactions to many fields, including protein-protein interactions, allostery, protein evolution and resistance. My central hypothesis is that we can use the exquisite sensitivity of water molecules to contextual changes in our favor. The hypothesis that water fluctuations report on changes in dynamic features will be exploited in three specific areas via perturbation with 1) temperature, 2) mutation and 3) ligands. 1) Re-defining water networks in protein structures: I hypothesize that physiological temperatures provide a less distorted view of water networks within protein crystals than structures obtained using common cryogenic freezing. We will test the hypothesis by solving crystal structures of proteins over a range of temperatures. By exposing freezing artifacts, we can reveal hidden changes in water network dynamics that can be used productively to predict binding affinities. 2) Exploring isoform-specific differences in water networks: I hypothesize that by using water perturbations as a reporter for change, we can distinguish near-identical Hsp90 isoforms. We will test the hypothesis by tracking how co-evolved water networks respond to perturbations in a context-dependent manner. This will expose subtle differences in isoforms that the Hsp90 field has struggled to exploit for decades to explore differential isoform biology in disease. 3) Considering water network dynamics in ligand discovery: I hypothesize that including experimental water network terms will improve computational docking. Based on our previous success of including computationally derived solvation energies, we expect that this will lead to novel Hsp90 ligands that minimize water perturbation, which cannot be discovered otherwise.

项目概要/摘要水赋予生命。以至于寻找外星生命就是寻找液态水。然而，总的来说，陆地药物的发现仍然忽略了水分子。原因在于复杂性和尽管其表面上很简单，但它对生物分子相互作用的贡献具有多功能性。我之前的研究有研究了水在配体识别和选择性中的作用及其改善配体发现的效用。最近，我的实验室在水网络的流动性和配体结合的亲和力之间建立了联系到蛋白质。更一般地说，这项工作强调了水网络响应的可利用敏感性蛋白质和配体的变化。我的长期目标是将原子尺度的水摆动与蛋白质的变化联系起来构象景观并最终影响机体适应性。为了实现这一目标，我渴望铺平道路对蛋白质功能的更动态的看法，整合了目前被忽视的蛋白质灵活性和保湿。这很重要，因为构成蛋白质数据库 95% 的低温结构，提供扭曲的静态图像，然后用于设计配体。拟议工作的目标是制定一个务实的框架来定义和利用水网络动态。由于水无处不在在所有生物界面上都有发现，这个概念超越了蛋白质-配体相互作用扩展到许多领域，包括蛋白质-蛋白质相互作用、变构、蛋白质进化和抗性。我的中心假设是，我们可以利用水分子对环境变化的敏锐敏感性我们的青睐。水波动报告动态特征变化的假设将被利用通过 1) 温度、2) 突变和 3) 配体扰动三个特定区域。 1）重新定义水蛋白质结构中的网络：我假设生理温度提供了一个较少扭曲的观点蛋白质晶体内的水网络与使用普通低温冷冻获得的结构相比。我们将测试通过解析一定温度范围内蛋白质的晶体结构来验证这一假设。通过暴露冷冻人工制品，我们可以揭示水网络动态中隐藏的变化，这些变化可以有效地用于预测结合亲和力。 2）探索水网络中异构体特异性差异：我假设通过使用水作为变化报告者的扰动，我们可以区分几乎相同的 Hsp90 亚型。我们将测试通过跟踪共同进化的水网络如何响应上下文相关的扰动来提出假设方式。这将暴露 Hsp90 领域一直难以利用的异构体的细微差异几十年来探索疾病中的差异亚型生物学。 3) 考虑配体中的水网络动力学发现：我假设包括实验水网络术语将改善计算对接。基于我们之前包含计算得出的溶剂化能的成功，我们预计这将导致新的 Hsp90 配体最小化水扰动，这是其他方式无法发现的。