Computer Simulations of G-proteins and Molecular Machines

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The understanding of how active processes in the cell govern and control major biological functions, such as signaling and molecular motors, is a central question in biophysics. For example, a detailed understanding is needed of the control and mediation of life processes by G-proteins, where complexes of these proteins with their cofactors regulate signal transduction and transport processes in the cell. Similarly, it is important to understand how ATP is used to fuel biological machines and control key cellular processes. A detailed understanding is also needed for the origin of the directional motions of biological motors that generate forces in muscular, cardiac and neural cells. Progress in understanding these processes require a close interaction between theory and experiment. This project aims to elucidate how biological molecules control cellular function at the molecular level using state of the art computational approaches using experimental data to validate the findings. Outcomes of this project will be disseminated via general scientific lectures and outreach activities. In addition, simulation packages will be made available to the scientific community. Powerful multiscale models, including quantum mechanics/molecular mechanics (QM/MM) approaches for exploring chemical processes in G-proteins and coarse grained models for studies of energy transduction have been previously developed by the investigator and his research group. Such developments will now be used to quantify the chemical and conformational coupling in the motor protein F1-ATPase and to explore the force generation in myosin and its relationship to muscles action. In addition, the allosteric activation process of GPCRs and its effect on the binding of GDP and GTP to G-proteins, as well as the action of EF-Tu and EF-G, which play major role in controlling the ribosome function, will be explored. The detailed quantitative understanding resulting from this project is likely to have a strong impact on advancing fundamental biological knowledge, as well as having potential biomedical implications.