Computer Simulation of Electron and Proton Transfer

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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