Electrostatic modulation of protein dynamics and interactions (Supplement for Equipment Purchase)

蛋白质动力学和相互作用的静电调节（设备购买补充）

• 批准号: 9894611
• 负责人: Jana Shen
• 金额: $ 10.53万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894611
• 关键词: Affinity; Alzheimer' s Disease; Aspartic Endopeptidases; Benchmarking; Binding; Code; Communities; Coupled; Data; Dependence; Development; Drug Design; Drug Targeting; Electrostatics; Elevator; Equilibrium; Free Energy; Goals; Health; Histidine; Hybrids; Hypertension; Ice; Integral Membrane Protein; Ion Channel; Ions; Kinetics; Knowledge; Letters; Malignant Neoplasms; Mediating; Membrane; Membrane Potentials; Modeling; Molecular; Molecular Conformation; Pathway interactions; Peptide Hydrolases; Phosphotransferases; Population; Process; Protein Dynamics; Proteins; Protocols documentation; Proton-Motive Force; Protons; Sodium; Sodium-Hydrogen Antiporter; Solvents; Speed; Structure; Structure-Activity Relationship; Techniques; Testing; Transport Process; Validation; Walkers; antiporter; base; beta-site APP cleaving enzyme 1; computer studies; drug discovery; efflux pump; equipment acquisition; experience; innovation; insight; molecular dynamics; neglect; novel; pH gradient; protonation; secretase; simulation; small molecule; small molecule inhibitor; src-Family Kinases; stoichiometry; temporal measurement; tool

Project Summary/Abstract This renewal proposal seeks to continue the development and application of continuous constant pH molecular dynamics (CpHMD) tools to advance molecular understanding of proteases, kinases and sodium/proton an- tiporters which are involved in Alzheimer's disease, cancer and hypertension, respectively. The objectives of this proposal are to 1) further develop, accelerate and disseminate CpHMD; 2) discover electrostatic modulators of aspartyl proteases and kinases towards selective inhibition; and 3) elucidate the mechanisms of sodium/proton antiporters. Development of a pH stat to properly control solution pH has been a long-standing goal in the MD community. Our recent development of PME-based all-atom CpHMD brought us closer to the goal. In Aim 1, we will add a polarizable force field to take the accuracy of CpHMD to the next level. We will implement CpHMD in other packages to enable alternative implicit-solvent models and force fields. We will implement the code on the GPU platform to allow routine microsecond-scale simulations. The new developments will push the boundary of current MD simulations, transforming pKa calculations and studies of proton-mediated processes. Protonation states and pH effects are a neglected aspect in structure-based drug design due to the lack of tools and understanding. We recently discovered a pH-regulated dynamics-activity relationship for -secretase (a major Alzheimer's drug target) and demonstrated significant pH dependence in small-molecule binding. In Aim 2, we will continue the study of -secretase related aspartyl proteases, and we will tackle challenging questions regarding kinase activation and selective inhibition. Conventional fixed-protonation-state MD with static-structure-based electrostatic calculations cannot reliably iden- tify proton-binding residues and elucidate proton-coupled conformational dynamics. We recently developed the membrane hybrid-solvent CpHMD, which allowed the first constant pH simulations of a proton channel (M2), a sodium/proton antiporter (NhaA) and an efflux pump (AcrB). In Aim 3, we plan to apply this and the new tools developed in Aim 1 to gain further insights into the sodium-proton exchange process in NhaA and to elucidate the distinctive mechanism of another sodium-proton antiporter. These studies will further validate CpHMD and establish it as a powerful tool for studies of proton-coupled transmembrane proteins. In summary, the proposed project will push the boundary of the current predictive power of molecular simulations, transform studies of proton-mediated processes, and generate new insights to accelerate drug discovery targeting Alzheimer's disease, cancer and hypertension.

项目总结/摘要 本更新建议旨在继续开发和应用连续恒pH分子 动力学（CpHMD）工具，以推进蛋白酶，激酶和钠/质子和 这些转运蛋白分别与阿尔茨海默病、癌症和高血压有关。这一目标 建议是：1）进一步开发、加速和推广CpHMD; 2）发现 乙酰化蛋白酶和激酶的选择性抑制; 3）阐明钠/质子的机制 反向转运体 开发一种pH统计器来适当地控制溶液pH一直是MD社区的长期目标。 我们最近开发的基于质子交换膜的全原子CpHMD使我们更接近这一目标。在目标1中，我们将添加 一个可极化的力场，将CpHMD的准确性提升到一个新的水平。我们将在其他领域实施CpHMD 软件包，使替代隐式溶剂模型和力场。我们将在GPU上实现代码 该平台允许常规微秒级模拟。新的发展将推动当前的边界 分子动力学模拟，转化pKa计算和质子介导过程的研究。 在基于结构的药物设计中，由于缺乏工具，质子化状态和pH效应是一个被忽视的方面 和理解我们最近发现了一种pH调节的β-分泌酶（a 主要的阿尔茨海默病药物靶点），并在小分子结合中表现出显著的pH依赖性。在Aim中 2、我们将继续研究与β-分泌酶相关的酰基蛋白酶，并将解决具有挑战性的问题。 关于激酶激活和选择性抑制。 传统的固定质子化状态MD与基于静态结构的静电计算不能可靠地确定- 验证质子结合残基并阐明质子耦合构象动力学。我们最近开发了 膜混合溶剂CpHMD，允许质子通道（M2）的第一个恒定pH模拟， 钠/质子反向转运体（NhaA）和射束泵（AcrB）。在目标3中，我们计划应用这一点和新工具 在目标1中开发，以进一步了解NhaA中的钠质子交换过程，并阐明 另一种钠质子反向转运蛋白的独特机制这些研究将进一步验证CpHMD， 建立它作为一个强有力的工具，质子耦合跨膜蛋白的研究。 总之，拟议的项目将突破分子模拟当前预测能力的界限， 改变质子介导过程的研究，并产生新的见解，以加速药物发现靶向 老年痴呆症癌症和高血压。