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.
|Kim, Ilsoo; Warshel, Arieh (2016) A Microscopic Capacitor Model of Voltage Coupling in Membrane Proteins: Gating Charge Fluctuations in Ci-VSD. J Phys Chem B 120:418-32|
|Kim, Ilsoo; Warshel, Arieh (2016) Analyzing the electrogenicity of cytochrome c oxidase. Proc Natl Acad Sci U S A 113:7810-5|
|Vorobyov, Igor; Kim, Ilsoo; Chu, Zhen T et al. (2016) Refining the treatment of membrane proteins by coarse-grained models. Proteins 84:92-117|
|Lameira, Jeronimo; Bora, Ram Prasad; Chu, Zhen T et al. (2015) Methyltransferases do not work by compression, cratic, or desolvation effects, but by electrostatic preorganization. Proteins 83:318-30|
|Kim, Ilsoo; Warshel, Arieh (2015) Equilibrium fluctuation relations for voltage coupling in membrane proteins. Biochim Biophys Acta 1848:2985-97|
|Alhadeff, Raphael; Warshel, Arieh (2015) Simulating the function of sodium/proton antiporters. Proc Natl Acad Sci U S A 112:12378-83|
|Kim, Ilsoo; Warshel, Arieh (2014) Coarse-grained simulations of the gating current in the voltage-activated Kv1.2 channel. Proc Natl Acad Sci U S A 111:2128-33|
|Vicatos, Spyridon; Rychkova, Anna; Mukherjee, Shayantani et al. (2014) An effective coarse-grained model for biological simulations: recent refinements and validations. Proteins 82:1168-85|
|Warshel, Arieh (2014) Multiscale modeling of biological functions: from enzymes to molecular machines (Nobel Lecture). Angew Chem Int Ed Engl 53:10020-31|
|Kim, Ilsoo; Chakrabarty, Suman; Brzezinski, Peter et al. (2014) Modeling gating charge and voltage changes in response to charge separation in membrane proteins. Proc Natl Acad Sci U S A 111:11353-8|
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