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 solvent description to predict protein structure, as well as multiprotein complexation and aggregation. A detailed understanding of aqueous solutions and their effects on biomolecules is needed to expedite future improvements to such a continuum representation (Hassan, 2014). We utilize ab-initio quantum chemistry 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 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 built models for intramural colleagues. A paper written in collaboration with NIAID is now in press (Kuhns et al.), and another manuscript has been submitted for publication in collaboration with NHGRI. We are working with NIDDK to study protein-RNA interfaces using computational analyses and experimental verification. With colleagues at NIBIB, we have studied gold nanoparticles 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. We have studied ultrasmall gold nanoparticles covered with GHS, in physiological fluids, in serum, and biological saline solutions, to rationalize experimental observations regarding their aggregation. A paper was published, and an oral presentation was delivered at the National Meeting of the Biophysical Society. In collaboration with NIMH, 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. One paper was published, and another is in preparation. In addition, we are investigating the binding modes of peripheral benzodiazepine receptor ligands now known as translocator protein ligands via MD simulations. This approach should 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 devoid of addiction. A manuscript 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 chemistry, in pursuit of designing better drugs to combat tuberculosis. A manuscript is in preparation. With NHLBI, we have investigated the structure and energetics of polymethylated 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) ligand complexed with lanthanide ions. These complexes will find application in both magnetic resonance imaging and protein-structure studies. One paper was published. With NCI, we have investigated the geometry and energetics of 89Zr complexes. These 89Zr complexes are being synthesized and will be used as radiotracers for imaging tumors of interest with PET. The US patent applications for the novel Zr based-radiotracers was published. We have also carried out quantum chemical calculations to investigate the mechanism of radiolabeling iodides/astatides of bioactive compounds for tumor treatments. One paper was published, and another manuscript is being prepared. A European patent application entitled Method for Synthesizing Iodo- or Astatoarenes Using Diaryliodonium Salts has also been filed. With NICHD, we continue using MC and MD 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 (Cardone, Pant, and Hassan, 2013) 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 was published. 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 current continuum methodologies for treating 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 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. In collaboration with NIST, we are studying the separation and purification of carbon nanotubes (CNT) using DNA and RNA chains. We use Monte Carlo (MC) and molecular dynamics (MD) simulations to establish a protocol that can be used experimentally to separate CNT of specific properties to be used for delivery and for other biotechnological applications. A manuscript is in preparation. We have improved the program MemExp, which has been used my researchers around the world since 2002, to facilitate the analysis of a wider range of kinetics experiments. A manuscript is being prepared in collaboration with physicists at the University of Illinois at Chicago, and a new version of the program will be released soon.
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