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. 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 halides 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 are 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, such as and opioid receptors, 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. Models have been built for intramural colleagues. A paper has been submitted in collaboration with NICHD, and a manuscript is in preparation that describes a collaboration with NIAID. We are also working with NIDDK to study protein-RNA interfaces using computational analyses and experimental verification. Given the increasingly important role of nanotechnology in biomedicine, we have started a number of computational studies on the microscopic origin of nanocrystal formation. 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. A publication is to be submitted shortly. 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. A manuscript is in preparation. In addition, we have investigated the binding modes of peripheral benzodiazepine receptor ligands now known as translocator protein ligands. 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 (Magn. Reson. Chem. 2013), and another is being prepared. 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 chemstry, in pursuit of designing better drugs to combat tuberculosis. One manuscript is in preparation. With NCI, we have investigated the geometry and energetics of 89Zr complexes. These 89Zr 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 one paper was published (Chem. Commun. 2013). A patent application for the novel Zr based-radiotracers was also submitted, and another manuscript concerning design and synthesis of Zr(IV) complexes exhibiting high kinetic inertness is in preparation. We have also carried out quantum chemical calculations to probe the mechanism of insertion of radiolabeled halides into bioactive compounds for tumor imaging. 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. A paper has been submitted. 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. One paper has been submitted and, a second manuscript is in preparation. 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 manuscript describing the computational aspects of the multi-grid method is currently being written.

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Haskali, Mohammad B; Telu, Sanjay; Lee, Yong-Sok et al. (2016) An Investigation of (Diacetoxyiodo)arenes as Precursors for Preparing No-Carrier-Added [(18)F]Fluoroarenes from Cyclotron-Produced [(18)F]Fluoride Ion. J Org Chem 81:297-302
Opina, Ana Christina L; Strickland, Madeleine; Lee, Yong-Sok et al. (2016) Analysis of the isomer ratios of polymethylated-DOTA complexes and the implications on protein structural studies. Dalton Trans 45:4673-87
Cardone, A; Brady, M; Sriram, R et al. (2016) Computational study of the inhibitory mechanism of the kinase CDK5 hyperactivity by peptide p5 and derivation of a pharmacophore. J Comput Aided Mol Des 30:513-21
Guérard, François; Lee, Yong-Sok; Baidoo, Kwamena et al. (2016) Unexpected Behavior of the Heaviest Halogen Astatine in the Nucleophilic Substitution of Aryliodonium Salts. Chemistry 22:12332-9
Cardone, Antonio; Bornstein, Aaron; Pant, Harish C et al. (2015) Detection and characterization of nonspecific, sparsely populated binding modes in the early stages of complexation. J Comput Chem 36:983-95
Iyer, Malliga R; Cinar, Resat; Liu, Jie et al. (2015) Structural Basis of Species-Dependent Differential Affinity of 6-Alkoxy-5-Aryl-3-Pyridinecarboxamide Cannabinoid-1 Receptor Antagonists. Mol Pharmacol 88:238-44
Bhirde, Ashwinkumar A; Hassan, Sergio A; Harr, Erick et al. (2014) Role of Albumin in the Formation and Stabilization of Nanoparticle Aggregates in Serum Studied by Continuous Photon Correlation Spectroscopy and Multiscale Computer Simulations. J Phys Chem C Nanomater Interfaces 118:16199-16208
Falcon, Jack; Coon, Steven L; Besseau, Laurence et al. (2014) Drastic neofunctionalization associated with evolution of the timezyme AANAT 500 Mya. Proc Natl Acad Sci U S A 111:314-9
Kang, J-H; Hassan, S A; Zhao, P et al. (2014) Impact of subdomain D1 of the short form S1b of the human prolactin receptor on its inhibitory action on the function of the long form of the receptor induced by prolactin. Biochim Biophys Acta 1840:2272-80
Hassan, Sergio A (2014) Implicit treatment of solvent dispersion forces in protein simulations. J Comput Chem 35:1621-9

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