Computer Simulation of Electron and Proton Transfer

描述（由申请人提供）：控制电子、质子和离子转运的蛋白质支持活细胞的基本功能，对许多生命过程至关重要。例如，电子转移（ET）和质子运输（PTR）联合收割机产生跨膜的电化学梯度，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相关，因此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-功能相关性的方法来增强结构和生物化学研究的进展，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。方法开发和验证的重大进展，以及关键系统的试点研究已经将这项研究工作置于一个关键的位置，它可以在提供PTR，离子转运和ET的定量结构功能相关性方面取得进展。因此，提出了以下方向的平行进展：目标1 -生物PTR -在赠款中开发的方法允许一个量化的关键质子传导系统的行动。因此，拟议的项目包括：（一）探索细胞色素C氧化酶（CcO）的门控机制，同时侧重于明确的质子通道。(ii)我们最近在模拟pH梯度转换为矢量旋转的F0-ATP酶的突破将被量化，努力获得更好的理解质子路径。(iii)电压激活PTR在Hv 1将探讨（iv）粗粒（CG）建模的膜电位的进展将被利用在解释所观察到的膜电位的影响和PT路径之间的关系在CcO。(v)细菌视紫红质的早期PTR的研究将被扩展，重点是后续步骤。目的2 -生物控制离子转运-我们在CG建模的膜电位的进展将被利用在电压激活的离子通道的作用和离子通道的选择性控制的进一步研究。目的3- ET过程-将探索CcO中的ET和ET/PT。目标4-确认-将对不同型号进行关键确认。

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.