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 is in press (Hassan and Mehler). 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. In collaboration with NCI, we published a study in which homology modeling was used to investigate genetic mutations associated with skin disease (Herman et al.). Also with NCI, we modeled the SH2 domain of the tensin-3 protein as part of a study published in Cancer Cell (Qian et al.). Other proteins have also been modeled, and new collaborations are anticipated. In collaboration with NIMH and NHLBI, we are utilizing ab-initio quantum chemical calculations to elucidate the mechanism of the fluorination of diaryliodonium, which is essential in the development of novel PET ligands. In this endeavor, one paper has been completed and three are in preparation. With NIDA, we have proposed the structure-activity relationships of opioid-receptor ligands, in attempts to design and synthesize novel opioid analgesics. Three papers have been published. In particular, the 2009 paper (Zhang et al.) was published in the centennial issue of the Journal of Medicinal Chemistry. In addition, another manuscript has been completed. Ongoing collaborative research with NCI includes the design and synthesis of a new series of HSP90 inhibitors. 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 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. A manuscript is in preparation.
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