Computer Simulation of Electron and Proton Transfer

电子和质子转移的计算机模拟

• 批准号: 8575914
• 负责人: ARIEH WARSHEL
• 金额: $ 31.27万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8575914
• 关键词: Accounting; Arrhythmia; Bacteriorhodopsins; Biochemical; Biological; Carrier Proteins; Cells; Cereals; Charge; Chemicals; Computer Simulation; Coupled; Cytochromes; Dependence; Development; Diabetes Mellitus; Disease; Electrodes; Electrolytes; Electron Transport; Electrons; F0 ATPase; Generations; Gramicidin; Grant; Ion Channel; Ion Transport; Ions; Kv1.2' channel; Life; Malignant Neoplasms; Membrane; Membrane Potentials; Membrane Proteins; Methods; Modeling; Molecular; Mutation; Osteoporosis; Oxidases; Oxidation-Reduction; Pathway interactions; Pharmaceutical Preparations; Pilot Projects; Play; Positioning Attribute; Process; Proteins; Proton Pump; Protons; Reaction; Research; Role; Rotation; Signal Transduction; Simulate; Staging; Structure; System; Therapeutic Intervention; Time; Transport Process; Ulcer; Validation; Water; Work; arm; base; biological systems; cytochrome c oxidase; drug development; drug discovery; fighting; frontier; method development; multi-scale modeling; operation; pH gradient; public health relevance; relating to nervous system; simulation; synergism; tool; validation studies; voltage; water channel

DESCRIPTION (provided by applicant): Proteins that control the transport of electrons, protons and ions underpin basic functions of living cells and are crucial to many life processes. For example, electron transfer (ET) and proton transport (PTR) combine to produce electrochemical gradients across membranes, which are then used to produce ATP. Similarly, ion channels play a vital role in neural signal transduction and other functions. Since mutations that disrupt the action of such proteins are associated with many diseases, these proteins present major targets for therapeutic intervention and play a central role in drug discovery efforts. However, further advances in rational drug development should be helped significantly by augmenting the progress in structural and biochemical studies by approaches that would provide the needed quantitative structure- function correlations. Thus, it is important to develop, refine and apply quantitative computer simulations tools for this purpose. Major progress in method development and validation, as well as pilot studies of key systems have placed this research effort in a pivotal position, where it can progress in providing quantitative structure function correlations of PTR, ion transport and ET. Thus, parallel advances in following directions are proposed: Aim 1 - Biological PTR - The method developed in the grant allows one to quantify the action of key proton-conducting systems. Thus, the proposed projects include: (i) Exploring the gating mechanism of the Cytochrome C oxidase (CcO), while focusing on well-defined proton channels. (ii) Our recent breakthrough in modeling the conversion of pH gradients to vectorial rotation in the F0-ATPase will be quantified, striving to gain a better understanding of the proton paths. (iii) The voltage activated PTR in Hv1 will be explored (iv) The progress in coarse grained (CG) modeling of the membrane potential will be exploited in interpreting the observed relationship between the effect of the membrane potential and the PT paths in CcO. (v) The study of the early PTR in bacteriorhodopsin will be extended, focusing on subsequent steps. Aim 2 - Biological control of ion transport - Our advances in CG modeling of the membrane potential will be exploited in further studies of the action of voltage-activated ion channels and the control of selectivity of ion channels. Aim3 - ET Processes - ET and ET/PT in CcO will be explored. Aim4 - Validations - Crucial validation of the different models will be conducted. 1

描述（由申请人提供）：控制电子、质子和离子传输的蛋白质支撑着活细胞的基本功能，对许多生命过程至关重要。例如，电子传递 (ET) 和质子传递 (PTR) 结合产生跨膜电化学梯度，然后用于产生 ATP。同样，离子通道在神经信号转导和其他功能中发挥着至关重要的作用。由于破坏此类蛋白质作用的突变与许多疾病有关，因此这些蛋白质是治疗干预的主要目标，并在药物发现工作中发挥着核心作用。然而，通过提供所需的定量结构-功能相关性的方法来促进结构和生化研究的进展，应该会大大有助于合理药物开发的进一步进展。因此，重要的是要发展， 为此目的完善和应用定量计算机模拟工具。方法开发和验证方面的重大进展以及关键系统的试点研究使这项研究工作处于关键地位，可以在提供 PTR、离子输运和 ET 的定量结构功能相关性方面取得进展。因此，提出了以下方向的并行进展： 目标 1 - 生物 PTR - 拨款中开发的方法允许人们量化关键质子传导系统的作用。因此，拟议的项目包括： (i) 探索细胞色素 C 氧化酶 (CcO) 的门控机制，同时重点关注明确的质子通道。 (ii) 我们最近在模拟 pH 梯度到 F0-ATPase 中矢量旋转的转换方面取得的突破将被量化，努力更好地了解质子路径。 (iii) 将探索 Hv1 中的电压激活 PTR (iv) 将利用膜电位粗粒度 (CG) 建模的进展来解释观察到的膜电位效应与 CcO 中 PT 路径之间的关系。 (v) 将扩展细菌视紫红质早期 PTR 的研究，重点关注后续步骤。目标 2 - 离子传输的生物控制 - 我们在膜电位 CG 建模方面的进展将用于进一步研究电压激活离子通道的作用和离子通道选择性的控制。目标 3 - ET 过程 - 将探讨 CcO 中的 ET 和 ET/PT。目标 4 - 验证 -将对不同模型进行关键验证。 1