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.

National Institute of Health (NIH)
Center for Information Technology (CIT)
Intramural Research (Z01)
Project #
Application #
Study Section
Special Emphasis Panel (CMM)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Center for Information Technology
United States
Zip Code
Douglass, Jacqueline; Gunaratne, Ruwan; Bradford, Davis et al. (2012) Identifying protein kinase target preferences using mass spectrometry. Am J Physiol Cell Physiol 303:C715-27
McQueen, Philip G (2010) Population dynamics of a pathogen: the conundrum of vivax malaria. Biophys Rev 2:111-120
Xie, Y-L; Hassan, S A; Qazi, A M et al. (2009) Intramolecular disulfide bonds of the prolactin receptor short form are required for its inhibitory action on the function of the long form of the receptor. Mol Cell Biol 29:2546-55
Berkower, Ira; Patel, Chiraag; Ni, Yisheng et al. (2008) Targeted deletion in the beta20-beta21 loop of HIV envelope glycoprotein gp120 exposes the CD4 binding site for antibody binding. Virology 377:330-8
Hassan, Sergio A (2008) Computer simulation of ion cluster speciation in concentrated aqueous solutions at ambient conditions. J Phys Chem B 112:10573-84
Balla, Andras; Tuymetova, Galina; Toth, Balazs et al. (2008) Design of drug-resistant alleles of type-III phosphatidylinositol 4-kinases using mutagenesis and molecular modeling. Biochemistry 47:1599-607
Zezula, Josef; Singer, Lisa; Przybyl, Anna K et al. (2008) Synthesis and pharmacological effects of the enantiomers of the N-phenethyl analogues of the ortho and para e- and f-oxide-bridged phenylmorphans. Org Biomol Chem 6:2868-83
Lee, Yong-Sok; Pike, Victor W; Hodoscek, Milan (2008) Identification of the transition states in the inversion of 1,4-benzodiazepines with the ab initio replica path method. J Phys Chem A 112:1604-11
Hassan, Sergio A (2008) Morphology of ion clusters in aqueous electrolytes. Phys Rev E Stat Nonlin Soft Matter Phys 77:031501
Pavlicek, Jiri; Coon, Steven L; Ganguly, Surajit et al. (2008) Evidence that proline focuses movement of the floppy loop of arylalkylamine N-acetyltransferase (EC J Biol Chem 283:14552-8

Showing the most recent 10 out of 44 publications