ME Seminar: Molecular mechanism of membrane targeting by GRP1 PH domain
Details of the next seminar in Mechanical Engineering Department are given below.
Title: Molecular mechanism of membrane targeting by GRP1 PH domain
Speaker: Dr. Anand Srivastava
Department of Chemistry,
Institute for Biophysical Dynamics and Computation
University of Chicago
Date : Wednesday, November 14, 2012
Time : 3:30 P.M.
Venue : FB-364(ME seminar room)
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Title:
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Molecular mechanism of membrane targeting by GRP1 PH domain
Abstract:
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Pleckstrin-homology (PH) domains are one of the most common membrane targeting motifs in intercellular signalling proteins. GRP1 PH domain
selectively binds to a special class of rare charged phospholipids, viz. phosphatidylinositol (3,4,5)-trisphosphate (PIP3). Besides the highly
electronegative PIP3 lipids, there are various other factors that are not well understood in the signalling process. Guided by electron paramagnetic resonance (EPR) experiments to recreate the initial PH domain docking geometry, we carried out all-atom MD simulations to understand the mechanism by which the PH domain and PIP3 lipids participate in intercellular signalling processes. Role of other phospholipids are also explored. MD simulations reveal several important insights at membrane protein binding interfaces. Moreover, atomistic MD simulations also show that within a given simulation time (on the order of hundreds of nanoseconds), GPR1 PH domain relaxes to different docking geometry in response to the local changes in lipid composition. Mutations that may guide and expedite experiments to verify the docking geometry predictions are also proposed and will be discussed.
In the second part of the talk, an enhanced multiscale coarse grained (MS-CG) model being developed to study the above membrane protein system
will be presented. To capture the electrostatic search and binding mechanism in membrane-PH domain systems at experimentally relevant length
and time scales, solvent-free CG models for lipids and proteins are developed such that the critical electrostatic features can be explicitly
represented with as few coarse-grained sites as possible. In the MS-CG process, the CG interactions potential is assumed as an arbitrary function of unknown variables. The final CG site-site interactions are obtained by variational principle where the residual of the forces from the assumed field is minimized with the reference forces from the all-atom simulations. In this work, improvements in the MS-CG method are being made for anionic lipids by incorporating the screened electrostatic interaction separately. Methodological details about the ongoing
coarse-graining work will be discussed.
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Brief Bio:
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Dr. Anand Srivastava obtained his bachelors and doctoral degree from IIT Kharagpur and Ohio State University, respectively. Presently he is a
post-doctoral fellow in Physical Sciences at University of Chicago. His current research interests are developing novel coarse-grained models for protein membrane systems, molecular mechanics of membranes, dynamics of retroviral Gag proteins with RNAs. During his doctorate as NSF PhD Fellow he studied bulk and finite polystyrene-CO2 binary systems using molecular dynamics. Dr. Srivastava has also worked as CAD Analyst and developer in Intergraph Consulting for two years.
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