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| Dr. Michael Pitman received his Ph.D. in Chemistry in 1995 from the University of California, Santa Cruz. Soon after, he joined IBM Research and continued working in the area of computational ligand design and optimization methodology, which served as one of the original focus areas of IBM's Computational Biology Center. In 2000, he began pursuing his interests in detailed simulation of membrane and membrane proteins. After joining the Blue Gene Protein Science effort, he created the Membrane Protein Science Initiative, which is now one of the few chartered projects awarded unprecedented resource on the Blue Gene/W supercomputer at IBM's Watson Research Center. He presently leads the Membrane Protein Science effort at IBM's Computational Biology Center, coordinating collaborators across disciplines toward microsecond scale molecular dynamics simulations of membrane proteins. His current research focus is the mechanistic details of GPCR activation, where extended simulations are conducted to gain insight into and help interpret experimental data of structural and dynamical properties of GPCRs in native-like membrane environments.
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Exploring Rhodopsin Activation with Large Scale Molecular Dynamics
Mike Pitman, IBM
Light activates rhodopsin through the isomerization of the retinal chromaphore from cis- to trans-retinal. What follows is series of structural transitions that are difficult to characterize experimentally. Several intermediates are spectroscopically distinct along the path to the G-Protein binding form, and substantial reorganization is indicated from a wide range of experimental observations. Simulating rhodopsin adjusting to trans-retinal in full atomic detail is an enormous computational challenge, and is the subject of an ongoing project hosted by the Blue Gene/W supercomputer.
This talk will summarize current results a series of rhodopsin simulations in an explicit membrane composition of 2:2:1 mixture of 1-stearoyl-2-docosahexaenoyl-phosphatidylethanolamine (SDPE), 1-stearoyl-2-docosahexaenoyl-phosphatidylcholine (SDPC), and cholesterol. Dark-adapted rhodopsin (PDB 1F88) was simulated for 120 ns prior to cis/trans isomerization, followed by a full microsecond of simulation with trans-retinal. Another series with dark-adapted rhodopsin (PDB 1U19) and 30 independently constructed membrane configurations were each simulated for 100 ns (totaling 3 microseconds). Several fascinating events occur on this timescale which may yield insights into the activation process and motivate specific experiments. DHA may play a more direct role in activation in addition to its effects on membrane properties, and protein fluctuations allow water channels to extend from the cytoplasmic side to the schiff base of trans-retinal.
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