We have continued to develop, implement, and apply simulation methods in computational studies of the energetics, dynamics, and mechanisms 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 an invited book chapter has been published (Hassan and Mehler). We also utilize ab-initio quantum chemical approach to investigate the geometry and energetics of bioactive compounds in ground and transition states. This approach is particularly useful in elucidating the transition states of chemical reactions of interest (e.g., diaryliodonium 18F-fluoride) that cannot be probed by experiments. The resulting transition-state information provides insight into the modulation of the product selectivity of reactions via chemical modifications. We have also been working to develop structure-prediction methods for application to peptides, protein-protein complexes, and G protein coupled receptors (GPCRs). Realistic models could be used to investigate the interactions of GPCRs with extracellular and intracellular signaling molecules. We also model proteins based on homology and have worked to improve the generation and refinement of such models. Several preliminary models have been built for intramural colleagues, and associated manuscripts are anticipated. In collaboration with NIMH and NHLBI, we have carried out ab-initio quantum chemical calculations to elucidate the fluorination mechanism of diaryliodonium salts at the atomic level. An understanding of this process is essential in the development of novel 18F-labeled PET probes for brain imaging. In this endeavor, we have related the radio-fluorinated product selectivity to the differences in activation free energies of the two respective transition states (Chun et al.). Also, based on the calculated stability of the dimeric 2-methylphenyl(2-methoxyphenyl)iodonium chloride, we have proposed that reactions of diaryliodonim halides with 18F ions require the dissociation of dimers to monomers to allow the replacement of chloride ions with 18F ions (Lee et al.) Two additional mechanism related papers are in preparation. With NIDA/NIAAA, we have proposed the structure-activity relationships of opioid-receptor ligands, in attempts to design and synthesize novel opioid analgesics. Two papers were published and another manuscript has been submitted. In particular, the 2009 paper (Zhang et al.) was published in the centennial issue of the Journal of Medicinal Chemistry. With NIAID, we are investigating the nitroimidazole reduction mechanism. This study utilizes the combined potentials of quantum mechanics and molecular mechanics, in pursuit of designing better drugs for tuberculosis. With NICHD, we published a paper 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 (Xie et al.). Prolactin is a hormone that has been implicated in the development of human breast tumors. With NINDS, we used 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. A paper was published (Cardone et al.).
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