Computationally Intensive Research Project
Computational Study of Protein-Protein Interaction Dynamics at Single Molecule Level
MSC News
Additional Information
Jin Wang,1 Peter Hong Lu,2 Qiang Lu1
1State University of New York at Stony Brook, 2Pacific Northwest National Laboratory
FY07 Allocation - 80,000
Abstract
Protein-protein interactions are extremely important and complex in living cells. Studying the dynamical processes of protein-protein interactions is crucial for uncovering the fundamental mechanisms and dynamics governing biological interactions and interfaces, such as cell signaling processes. It would also help the understanding of the complex biological network involving protein-protein interactions in bacterial cells. In this project, we plan to carry out a systematic simulation study on protein-protein interaction dynamics using the new parallel computation facility of EMSL at PNNL, which will support and be of synergy with the EMSL scientific theme on biological interactions and interfaces. Furthermore, the new capability and fundamental understanding developed in this project will significantly enhance our single-molecule spectroscopy studies on protein-protein interaction dynamics related to the EMSL Membrane Biology Grand Challenge (PNNL), EMSL Biogeochemistry Grand Challenge (PNNL), Genome-To-Life (DOE) and System Biology Initiative (LDRD; PNNL) projects.
The dynamic process of binding occurs in a wide dynamic range, including millisecond to second timescale range. To be able to connect and compare computational simulation results with the results from single molecule binding experiments, long time and multiple trajectories are needed so that reliable statistics can be applied to decipher the properties of physical observable. The traditional molecular dynamics simulations cannot be carried out through such a wide time scale range. We propose to achieve a long-time molecular dynamics simulation by describing the protein interactions in a coarse grained way at the residue and atomic contact level guided by energy landscape theory where the effects of water molecules can be included and native interactions are preferred. Therefore, the dynamical processes of protein conformational dynamics in protein-protein interactions can be probed thoroughly in the entire time domain. We plan to study the statistical kinetics and characterize the structural correlations among the complex kinetics and conformational changes, which will reveal the dynamical interplay of binding and conformational changes. It would also serve as an adequate computational template enabling further investigations on mechanisms of binding of different bio-molecular interacting complexes in vitro and in living cells.
We will use coarse grained molecular dynamics simulation to study flexible binding of Camodulin signaling. A single-molecule fluorescence resonance energy transfer (FRET) and polarization study of conformational dynamics of calmodulin (CaM) interacting with a target peptide, C28W of 28 amino-acid oligomer has been carried out at PNNL. The C28W peptide represents the essential binding sequence domain of the Ca-ATPase protein interacting with CaM, which is important in cellular signaling for the regulation of energy in cellular metabolism. However, the mechanism of the CaM-C28W recognition complex formation is still unclear without a MD simulation analysis. We will carry out detailed simulations to explore the role of flexibility of CaM binding with the target peptides, using our coarse grained Go model of molecular dynamics.
