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 was published in collaboration with NIAAA, in which protein and ligand modeling guided experiments to interpret the species-dependent differential affinity of cannnabinoid-1 receptor agonists (Iyer et al, 2015). We are 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 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 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 is in preparation, a meeting poster has been submitted, and another is to be submitted. 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 was submitted for publication, 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 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. 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 magnetic resonance imaging. A manuscript was submitted for publication. 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. Recently, the X-ray structure of Zr (IV) complexed with N-methylhydroxamic acids has been solved. Both US and foreign patent applications for the novel Zr based-radiotracers were submitted. We have also carried out quantum chemical calculations to probe the mechanism of insertion of radiolabeled halides into bioactive compounds for tumor imaging, and a manuscript is being prepared. 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. A paper was published (Cardone et al, 2015) and another was submitted. 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.
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