Simulating Protein Structures, Complexes, And Dynamics

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We have continued to develop, implement, and apply simulation methods in computational studies of the energetics and dynamics of biomolecular systems. We are working to refine a continuum description of macromolecular solvation in terms of polar, nonpolar, and solvent-structure effects. One manuscript has been published (J Phys Chem B, 2007), and another is in preparation. We also model proteins based on homology and work to improve the generation and refinement of such models. With NICHD, we have been studying the inhibitor sensitivities of type-III phosphatidylinositol 4-kinase enzymes, and a manuscript has been submitted. Collaborating with OD, we modeled a deletion mutant of the HIV envelope glycoprotein gp120 for which exposure of the CD4 binding site leads to enhanced binding of two monoclonal antibodies. A manuscript was submitted for this study. In collaboration with NIMH and NHLBI, we are about to submit a manuscript describing reliable ways of determining the transition state of peripheral benzodiazepine receptor ligands that are utilized as probes for brain imaging. With NIDA, we are studying the structure-activity relationships of opioid-receptor ligands. One paper has been published (J Med Chem, 2007), and another is nearly competed. Ongoing collaborative research with NCI includes the design and synthesis of a new series of HSP90 inhibitors. With NICHD, we are studying the dynamics and energetics of AANAT, the first enzyme in the serotonin-melatonin conversion pathway. Also with NICHD, we have been using Monte Carlo and molecular dynamics simulations to study the structural nature of prolactin-receptor interactions and the specificity of binding and recognition. Prolactin is a hormone that has been implicated in the development of human breast tumors. We have also been working to develop computational methods for obtaining reliable structures of G protein coupled receptors (GPCRs). Realistic models could be used to investigate the interactions of GPCRs with extracellular and intracellular signaling molecules.