Proteins that control proton translocation (PTR), electron transfer (ET) and ion transfer, underpin basic functions of living cells such as energy transduction, sensory perception, cell movement, nerve conduction and signaling. Thus, the defected versions of the corresponding proteins are major drug design targets. The breakthroughs in structural studies of membrane proteins have gradually led to the elucidation of the structures of several important types of proton pumps, electron pumps and ion channels, and to qualitative ideas about the ways these systems operate. Nevertheless, in many cases, a quantitative structure-function correlation is still missing and the factors that control the operation of such systems are still not entirely clear. We believe that computer aided structure-function correlation of charge transport proteins is essential for further advances in treating diseases that involve such systems. Our group has developed and validated a wide range of powerful strategies for modeling electron transfer, proton transfer and ion currents in biological systems. These developments include combinations of microscopic and macroscopic simulation approaches that allow one to explore passive and active charge transport processes in short and long time scales and to explore the relationships between the structure of charge transport proteins and their biological function. Thus, we have finally reached the stage where we can actually simulate the time dependence of PTR, ET and ion transport through proteins, using realistic yet practical methods, and where we can finally quantify the action of key charge transport systems. Here, we propose to push the frontiers of this field in the following directions: (i) Simulating PTR processes and the corresponding energetics in studies of key biological systems, (ii) Validating our PTR models by more explicit simulations, (iii) Continuing our studies of reaction centers by exploring the effects of mutations, the meaning of the observed dielectric effect, and the nature of the short-time relaxation processes, (iv) Studying reorganization energies in donor-acceptor protein complexes, (v) Quantifying our studies of the selectivity of biological ion channels, and (vi) Continuing our studies of key electrostatic problems.
Charge transport proteins that control the transport of electrons, protons and ions, play a crucial role in biological processes. For example, proton pumps regulate the electrochemical gradient that drives the transport of molecules across membranes, while ion channels play a vital role in neural signal transduction and other key functions. Mutations that disrupt the function of such systems are associated with many diseases and the corresponding proteins present major targets for therapeutic intervention as well as playing a central role in drug discovery efforts. Advanced treatments of defective charge transport proteins require a detailed understanding of the corresponding biological functions. Fortunately, the progress in the elucidation of the structure of membrane proteins has provided major relevant structural information. However, further advances require quantitative structure-function correlations. We believe that computer modeling approaches can provide the needed structure-function correlations, and we propose to push the frontiers in modeling the actual function of proton transfer, electron transfer and ion transfer proteins. The proposed studies should provide a better understanding of the molecular origin of the different modes of biological charge transport. This should assist in the development of effective drugs that will help to fight diseases that are associated with defective charge transport proteins.
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