The purpose of Computational Chemistry sub-Core is to provide computational/modeling support for the investigators within the Program Projects. Computational chemistry and molecular modeling techniques will be used to gain structural/functional insight into specific molecular interactions present in the biomolecular complexes studied within different projects of the PPG. This sub-Core will integrate experimental data produced by Projects and other Cores in the Program with theoretical methods in order to produce structural information needed to elucidate the nature of interactions in these biosystems and the relationship between their structure and function. For example, the sub-Core will provide atomistic models for biomolecular complexes like protein L13A-RNA complex, eNOS complex with HSP-90 and caveolin, and HDL-PON1-MPO complex, which are investigated in Projects 3, 2 and 1, respectively, using molecular visualization/building programs (Pymol, SwissPDBViewer, Autodock4 and Modeller), and hydrogen-deuterium exchange and small angle neutron and X-ray scattering calculations. The interaction interface between different components of the complexes will be constructed using docking (Autodock4). The docking experiments will identify specific interactions between amino acid residues for protein-protein complexes, or between RNA nucleotides with amino acid residues for RNA-protein complexes, or between amino acid residues and lipids for lipoproteins. All solvated systems will be subjected to molecular dynamics simulations. The trajectory resulted from the simulation will be analyzed to determine the change in the conformation during simulation, the change in the pattern of H-bonds and salt-bridges, the change in the secondary structure and so forth. To investigate conformational changes that occur on a microsecond scale and are important for the functionality of the biomolecular system, coarse-grained simulations will be performed in which atoms are grouped together in beads and a bead-to-bead simplified force field is used. The theoretical understanding resulted from the computational/modeling investigation will be further used by the Projects to design new experiments.
This sub-Core will provide modeling support in defining the detailed atomistic structures in solution for different protein-protein, protein-RNA and protein-lipid complexes investigated in Projects 1, 2 and 3. The sub-Core personnel will interact with other researchers working in the Projects in order to facilitate the design of new experiments suggested by theoretical insigths obained from the computational analyses.
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