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

Public Health Relevance

Charge transport proteins that control the transport of electrons, protons and ions play a crucial role in life processes. Mutations that disrupt the function of such systems are associated with major diseases, including neural disorders, diabetes, cardiac arrhythmia, cancer, osteoporosis and ulcers. The charge transfer proteins present major targets for therapeutic intervention and play a central role in drug discovery efforts. However, exploiting such possibilities requires the ability to convert structural informaton to a detailed understanding of the corresponding functions. We believe that computer modeling approaches can provide the needed structure-function correlations, and thus propose to continue to push the frontiers in modeling the actual function of proton transfer, electron transfe 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 provide a major help in rational development of effective drugs that will accelerate the progress in fighting diseases associated with defective charge transport systems. 1

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Preusch, Peter
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Schools of Arts and Sciences
Los Angeles
United States
Zip Code
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

Showing the most recent 10 out of 59 publications