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 the structure of proteins, multiprotein complexes, and aggregates. A detailed understanding of aqueous solutions and their effects on biomolecules is needed to expedite future improvements to such a continuum representation. We are developing an algorithm for the treatment of many proteins in a system, which provides insight into protein interaction networks and the effects of cooperativity in multiprotein complexation. A manuscript will be submitted soon. 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 fluoride and diaryliodonium astatide) 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 opioid receptors and cannabinoid receptors, with their respective agonists and antagonists. We also model proteins based on homology and have built models for intramural colleagues. A paper written in collaboration with NIAID and another written in collaboration with NHGRI were published. A third manuscript has been submitted. We are working with NIDDK to study protein-RNA interfaces using computational analyses and experimental verification. With colleagues at NIBIB and the University of Sao Paulo, Brazil, we have studied gold nanoparticles in serum and in cell media to predict best strategies for use 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 of multiprotein-multiparticle solutions. 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. Two papers were published, another was submitted, and an oral presentation is scheduled for the upcoming ACS meeting. 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. Ongoing studies of fluorination include the trifluoromethylation mechanism of aryliodonium salts with CuCF3. 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. We studied a series of phenylmorphans and showed that several residues have the potential to interact directly with the ligand to increase affinity and efficacy. We have extended the study to benzofuro-pyridine derivatives with high affinities and are currently studying morphine-like compounds in which small chemical substitutions lead to dramatic changes in receptor activity. One paper was published and another 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 are investigating the structure and energetics of polymethylated 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) ligand complexed with lanthanide ions. Quantum chemical calculations are being carried out to determine the structural requirements that modulate the thermochemical stability of one isomer over the other. These complexes may find application in both magnetic resonance imaging and protein-structure studies. With NCI, we have investigated the geometry and energetics of 89Zr complexes. These complexes are being synthesized and will be used as radiotracers for imaging tumors of interest with PET. One paper was published. We are also carrying out quantum chemical calculations to investigate the mechanism of radiolabeling iodides/astatides of bioactive compounds for tumor treatments. One manuscript was 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 carried out a set of simulations based on a recently reported computational method 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. We derived a pharmacophore for future virtual screening. 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. 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 has been submitted in collaboration with physicists at the University of Illinois at Chicago, and another is in preparation with collaborators at Florida State University. A new version of the program will be released soon.
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