Theoretical and computational study of electron transport and redox-driven proton

电子输运和氧化还原驱动质子的理论和计算研究

• 批准号: 8579750
• 负责人: ALEXEI A STUCHEBRUKHOV
• 金额: $ 22.16万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8579750
• 关键词: Aerobic; Apoptosis; Brain; Cell Aging; Cells; Collaborations; Complex; Coupled; Cysteine; Cytochrome c Reductase; Degenerative Disorder; Dependence; Development; Dissociation; Electron Transport; Electrons; Enzymes; Evaluation; Free Energy; Free Radicals; Freezing; Functional disorder; Generations; Goals; Heart; Human; Kinetics; Ligands; Maps; Mechanics; Membrane Part; Mitochondria; Modeling; Molecular; Molecular Conformation; NADH; Nature; Oxidation-Reduction; Oxygen; Peripheral; Production; Property; Protein Conformation; Proton Pump; Protons; Pump; Reaction; Reactive Oxygen Species; Relaxation; Respiratory System; Testing; Theoretical Studies; Theoretical model; Time; Water; Work; arm; base; cell age; computer studies; enzyme model; enzyme structure; molecular dynamics; operation; protonation; quantum; research study; simulation

The goal of this computational project is to advance understanding of the molecular mechanism of NADH dehydrogenase (Complex I) - an enzyme which is the entry point of the electron transport chain in the respiratory system of aerobic cells. It has been established that the enzyme pumps 4 protons per 2 electrons of each NADH oxidized, however the molecular mechanism of proton pumping remains unknown. The work includes collaboration with a leading experimental expert in the field, who recently solved the structure of the enzyme. We will test the hypothesis that electron tunneling along the chain of seven FeS clusters in the peripheral arm of the enzyme is coupled to a long-range conformational change which in turn is coupled to proton translocation in the membrane part of the enzyme; the conformational change is presumably induced by the dissociation of one of the cysteine ligands to the terminal N2 FeS center upon its reduction; the local structural relaxation around N2 is transmitted to the membrane part of the enzyme, and induces allosteric change responsible for proton pumping; the time-limiting step of electron tunneling along the chain of FeS clusters provides a kinetic gate necessary for operation of this conformation-driven proton pumping machine. The approach is based on atomistic and quantum mechanical simulations of electron and proton transport, using state-of-the art quantum tunneling calculations and molecular dynamics simulations.

这个计算项目的目标是促进对分子机制的理解。 NADH脱氢酶(复合体I)--一种电子的入口点 需氧细胞呼吸系统中的传输链。已经证实，这种酶 每个NADH被氧化时，每2个电子中有4个质子被泵浦，但其分子机制 质子泵浦仍然未知。这项工作包括与领先的实验机构合作 该领域的专家，他最近解开了这种酶的结构。 我们将测试这样一种假设，即电子沿着七个FeS团簇的链在 该酶的外周臂与长程构象变化相连，而后者又是 与酶的膜部分的质子转移相耦合；构象变化 推测是由半胱氨酸配体中的一个解离到末端的N2FeS引起的 以其还原为中心；围绕n2的局部结构松弛被传递到 酶的膜部分，并引起变构变化，负责质子泵； 沿FeS团簇链条电子隧穿的时间限制步骤提供了一个动力学门 对于这种构象驱动的质子泵送机的运行是必要的。 该方法是基于电子和质子的原子论和量子力学模拟。 使用最先进的量子隧道计算和分子动力学的传输 模拟。