We have used homology modeling and Monte Carlo (MC) simulation in concert with collaborators' binding-affinity experiments to predict the important intermolecular contacts in the docking of a 10-residue peptide to cyclin dependent kinase 5 (cdk5). A structural model of cdk5 was based on the known structure of a homologous protein, cdk2. MC runs were performed in which the peptide substrate was guided toward specific protein residues suggested by experiments. In turn, results of the modeling were used to suggest site-directed mutations followed by binding assays in an experimental/theoretical attempt to model the cdk5-peptide complex. A manuscript was submitted for publication.We have also introduced a novel empirical term in the potential energy function of the CHARMM program to favor phi-psi conformations observed by solid-state NMR in computer simulations. The local structural information obtained by solid-state NMR, along with the CHARMM force field, was used to investigate alternative conformations of the V3 loop of the HIV-1 gp120 protein. A manuscript was submitted for publication.We probed the structural consequences of a mutation in the protein ubiquitin C-terminal-hydrolase L1. This mutation has been identified in a family with Parkinson's disease. We performed multiple molecular dynamics simulations of the native and mutant proteins to assess differences in average structure and atomic fluctuation. A manuscript has been accepted for publication in Nature.We continue to study the dependence of simulated structure and dynamics on environmental considerations such as solvation. We are simulating myoglobin and other proteins in various environments (hydrated protein, protein in solution, protein in crystal). Simulations of dynamics at various temperatures address questions of basic biophysical interest and help characterize different simulation approaches.
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