Computer Simulation of Electron and Proton Transfer

描述(申请人提供)：控制电子、质子和离子传输的蛋白质是活细胞基本功能的基础，对许多生命过程至关重要。例如，电子转移(ET)和质子转移(PTR)结合在一起，在膜上产生电化学梯度，然后用来产生三磷酸腺苷。同样，离子通道在神经信号转导和其他功能中起着至关重要的作用。由于破坏这些蛋白质作用的突变与许多疾病有关，这些蛋白质是治疗干预的主要靶点，并在药物发现工作中发挥核心作用。然而，通过提供所需的定量结构-功能相关性的方法，加强结构和生化研究的进展，应该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， 为此目的改进和应用定量计算机模拟工具。在方法开发和验证方面的重大进展，以及对关键系统的初步研究，使这一研究工作处于关键地位，可以在提供PTR、离子转运和ET的定量结构功能关联方面取得进展。因此，建议在以下方向取得平行进展：目标1--生物PTR--赠款中开发的方法使人们能够量化关键的质子传导系统的行动。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，同时专注于明确定义的质子通道。(Ii)我们最近在模拟F0-ATPase中pH梯度到矢量旋转的转换方面的突破将被量化，努力更好地了解质子路径。(Iii)将探讨Hv1中电压激活的PTR。(Iv)将利用膜电位的粗粒度(CG)模拟的进展来解释所观察到的CcO中膜电位与PT路径之间的关系。(V)将扩大对细菌视紫红质早期PTR的研究，重点放在后续步骤上。目的2-离子转运的生物控制-我们在膜电位CG模拟方面的进展将被用于进一步研究电压激活离子通道的作用和控制离子通道的选择性。AIM3-ET过程-ET和CO中的ET/PT将被探索。AIM4-验证-将对不同模型进行关键验证。

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.