Computer Simulations of G-proteins and Molecular Machines

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Over the past several decades we have witnessed tremendous advances in the studies of the molecular basis of human health. However, detailed quantitative understanding is still in a crucial need. For example, understanding is needed of the control and mediation of life processes by G-proteins where the complexes of these proteins, with their cofactors, regulate signal transfer and transport processes in the cell. Equally important is the understanding of the use of the energy reach compound ATP in specialized proteins to fuel biological machines and to control key energy conversion processes. A related issue that requires detailed understanding, is the problem of directional motions of biological motors that generate directional force in muscular, cardiac, and neural cells that are often involved in diseases due to faulty functions. Similarly, the understanding of the action of G protein coupled receptors (GPCRs) is crucial for having a clearer view of the way external factors such as different hormones activate cellular process. The PI serves as “Science Ambassador” and engages with children and young adults to attract their interest in STEM areas.The PI has developed methods for studying phosphate hydrolysis reactions in solution, in RasGAP, in EF-Tu and in ATPases. Using these methods, the PI’s group explored the key role of mutations leading to cancer and identified the underlying allosteric mechanism as well as, the mechanism by which chemical energy is converted to work. ab initio QM/MM studies of the reference solution reaction and evaluation of the corresponding surface in G-proteins and ATPases were conducted in the PI’s laboratory. Similar studies were also done with the biological motors, F0F1-ATP synthase, and myosin V. The current projects will move in parallel on the following fronts: (i) continue studies of the action of molecular machines, examining the action of rotary motors, with focus on understanding the role of mutations on the efficiency of the motors; (ii) studies on the detailed action and unidirectionality of myosins; (iii) studies of GPCRs focusing on the activation pathways of the μ-opioid receptor; and (iv) systematic studies of G-proteins, exploring the action of EF-Tu by ab initio QM/MM and work to establish the allosteric control of the activation process. This project was funded by the Molecular Biophysics Cluster of the Molecular and Cellular Biosciences Division.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.