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. A simplified parameterization has been developed and used to predict structures of peptides and mini-proteins, and a manuscript has been submitted. 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. Two papers were submitted for publication, and a third is in preparation. 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 mechanistic understanding provides a firm structural/theoretical basis for controlling the ratio of the two possible 18F or 211At labeled products. 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. In collaboration with NHGRI, a paper was published describing the likely structural consequences of a mutation observed in a patient. A second manuscript was submitted detailing another patients mutations. 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 different chemical layers in physiological fluids, including serum and saline solutions, to rationalize experimental observations regarding their aggregation, kinetics, and biolocalization. Two papers were published, and two oral presentations were delivered at the 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. An oral presentation on the radio-fluorinated product selectivity was given at the 22nd International Symposium on Fluorine Chemistry at Oxford University. Ongoing studies of fluorination include the elucidation of the hydrocarbon fluorination catalyzed by CoF3 as well as the trifluoromethylation mechanism of aryliodonium salts with CuCF3. These studies will provide insight for the efficient synthesis of 11C-labeled fluoroform, e.g. 11CCHF3, for PET imaging. In addition, we are investigating the binding modes of peripheral benzodiazepine receptor ligands now known as translocator protein (TSPO) ligands via MD simulations. This approach should lead to the design of higher affinity radio-labeled TSPO ligands for the imaging of brain inflammation associated with stroke, dementia, and other mental disorders. We have also investigated the lack of blood-brain-barrier penetration of newly synthesized serotonin receptor radioligands by comparing their structures and energetics. A manuscript was submitted. 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. A manuscript is being prepared, and a poster presentation was given at the Gordon Research Conference on Heterocycles. 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. A manuscript is in preparation, and a poster presentation is scheduled for an upcoming conference. With NCI, we carried out quantum chemical calculations to investigate the mechanism of radiolabeling iodides/astatides of bioactive compounds for tumor treatments. One manuscript 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 metalloproteins. We have improved the program MemExp, which is used by researchers around the world to recover distributions of effective lifetimes from kinetics data. The zero-time shift can now be estimated in experiments that require deconvolution of an instrument response. In collaboration with physicists at the University of Illinois at Chicago, a paper was published, and a second manuscript has been submitted. Version 5.0 of the program was released.
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