We have continued to develop, implement, and apply simulation methods in computational studies of the energetics, dynamics, and mechanisms of biomolecules. 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. An invited book chapter describing these developments for computational study of cellular components and their assemblies has been published (Hassan and Mehler, 2011). A manuscript addressing water-exclusion and liquid-structure forces was also published (Hassan and Steinbach, 2011). We also utilize ab-initio quantum chemistry to investigate the geometry and energetics of bioactive compounds in both ground and transition states. This approach is particularly useful in elucidating the transition states of chemical reactions of interest (e.g., diaryliodonium 18F-fluoride and nitro-imidazole based anti-TB drugs) 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. Preliminary models have been built for intramural colleagues. Our analyses of protein structures have contributed to collaborations with NICHD and NHLBI. The first of these studies was published in Human Mutation in 2012, and the second will appear in Am. J. Physiol. Cell Physiol. Given the increasingly important role of nanotechnology in biomedicine, we have started a number of computational studies on the microscopic origin of nanocrystal formation, and a paper has been published (Hassan, 2011). The practical relevance of these studies is the identification of small molecules that either facilitate or inhibit aggregation, e.g., the formation of kidney stones. With colleagues at NIBIB, we started simulation studies of gold nanoparticle in serum and in cell media to predict best strategies for use of nanoparticles in drug delivery and imaging. We developed multi-scaling techniques to realistically represent in vivo media and are using these approaches to speed up both Monte Carlo and molecular dynamics simulations. 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. Two mechanism related papers are in preparation. In addition, we have investigated the peripheral benzodiazepine receptor ligands now known as translocator protein (TSPO) ligands, such as the isoquinoline carboxamide, PK 11195, via 1H- and 13C-NMR studies, together with quanum chemistry (ACS Chem. Neurosci., 2012). This approach may lead to the design of novel radioligands for brain imaging. With NIDA/NIAAA, we have proposed the structure-activity relationships of opioid-receptor ligands, in attempts to design and synthesize novel opioid analgesics. One paper was published (Eur. J. Med. Chem., 2012), and another is being reviewed. With NIAID, we are investigating the nitroimidazole reduction mechanism. This study utilizes the combined potentials of quantum mechanics and molecular mechanics, as well as ab-initio quantum chemsitry, in pursuit of designing better drugs to combat tuberculosis. Two paper were published ((FEBS Journal, 2012;Structure, 2012), and one manuscript is in preparation. With NCI, we have investigated the geometry and energetics of Zr complexes. These Zr complexes are being synthesized and will be utilized as radiotracers for imaging tumors of interest with PET. Recently, the X-ray structure of Zr (IV) complexed with N-methylhydroxamic acids has been solved, and a manuscript is in preparation. With NICHD, we continue 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. Several mutations suggested in our simulations have been explored experimentally. Together, simulation and experiment are providing insights into receptor formation and its interaction with the hormone. 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. Additional simulations have been performed to understand the dynamics of enzyme action on a number of short peptides. We continue to use computer methods to explore the interaction of kinases with pathological peptides related to neurodegenerative disease. We carried out a set of simulations based on a recently reported computational method (Hassan and Steinbach, 2011) to predict the structure of p5, a novel peptide found to inhibit amyloid formation in vivo. Unlike our previous study on CIP, which showed similar properties, p5 can cross the blood-brain barrier, making it suitable for design of peptide-mimetic drugs for the treatment of Alzheimer's and other brain pathologies. A paper is in preparation and a poster was presented in August 2012 at the 13th International Conference on Systems Biology in Toronto, Canada. With NINDS and NIST, we are developing software for calculation of electrostatic properties in systems with large and highly heterogeneous charge distributions. This would allow us to extend and improve upon current continuum methodologies to DNA and other bio-polyelectrolytes, as well as to increase accuracy in the calculation of redox potentials for electron transfer in metaloproteins. The method is based on a recent publication in the J. Chem. Phys. (Hassan, 2012) where the computational performance and stability of the method were assessed. A paper was published in Analytical Biochemistry describing a new and convenient approach for filtering artifacts from lifetime distributions inferred from kinetics data using the maximum entropy method (Steinbach, 2012).
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