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. A detailed understanding of aqueous solutions and their effects on biomolecules should expedite future improvements to a continuum description, and two papers have been published reporting atomistic simulations of ion clusters in solution (SA Hassan). We also model proteins based on homology and work to improve the generation and refinement of such models. With NICHD, we have published a study of the inhibitor sensitivities of type-III phosphatidylinositol 4-kinase enzymes (A Balla et al.). 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. This study was published in Virology (I Berkower et al.). Additional modeling studies of gp120 and of Venezuelan equine encephalitis (VEE) protease are in preliminary stages. With NCI, we are preparing a manuscript in which homology modeling is used to investigate genetic mutations associated with skin disease. In collaboration with NIMH and NHLBI, we published a study describing reliable ways of determining the transition state of peripheral benzodiazepine receptor ligands (YS Lee et al.). Building on this study, we are applying quantum mechanical calculations to understand the mechanisms involved in synthesizing novel PET ligands. With NIDA, we are studying the structure-activity relationships of opioid-receptor ligands, in attempts to design and synthesize novel opioid analgesics. One paper was published (J Zezula et al.), one has been submitted, and a third is in preparation. 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, and a paper was published (J Pavlicek et al.). Also with NICHD, we have submitted a manuscript for publication in which Monte Carlo and molecular dynamics simulations were used 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. With NINDS, we are using computer modeling to better understand the structural and dynamical basis for the function of cyclin-dependent kinase 5 (cdk5). The deregulation of cdk5 may be involved in neurodegenerative diseases such as Alzheimer's disease. 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.