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Computational Research in Molecular Chemistry
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Mapping the Allosteric Sites of the A2A Adenosine ReceptorCaliman, A.D., Y. Miao, J.A. McCammonChem. Biol. Drug Disc. In press (2017)    
The A2A adenosine receptor (A2AAR) is a G protein-coupled receptor that is pharmacologically targeted for the treatment of inflammation, sepsis, cancer, neuro-degeneration, and Parkinson’s disease. Recently, we applied long-timescale molecular dynamics simulations on two ligand-free receptor conformations, starting from the agonist-bound (PDB ID:3QAK) and antagonist-bound (PDB ID:3EML) X-ray structures. This analysis revealed four distinct conformers of the A2AAR: the active, intermediate 1, intermediate 2, and inactive. In this study, we apply the fragment-based mapping algorithm, FTMap, on these receptor conformations to uncover five non-orthosteric sites on the A2AAR. Two sites that are identified in the active conformation are located in the intracellular region of the transmembrane helices (TM) 3/TM4 and the G protein-binding site in the intracellular region between TM2/TM3/TM6/TM7. Three sites are identified in the intermediate 1 and intermediate 2 conformations, annexing a site in the lipid interface of TM5/TM6. Five sites are identified in the inactive conformation, comprising of a site in the intracellular region of TM1/TM7, and in the extracellular region of TM3/TM4 of the A2AAR.  We postulate that these sites on the A2AAR be screened for allosteric modulators for the treatment of inflammatory and neurological diseases.
Improvements to the APBS biomolecular solvation software suite.Jurrus, E., D. Engel, K. Star, K. Monson, J. Brandi, L.E. Felbergy, D. Brookesy, L. Wilson, J. Chen, K. Liles, M. Chun, P. Li, T. Dolinsky, R. Konecny, D.R. Koes, J.E. Nielsen, T. Head-Gordon, W. Geng, R. Krasny, G.W. Weir, M.J. Holst, J.A. McCammon, N.A. Baker.Protein Sci. in press (2017)    
The Adaptive Poisson-Boltzmann Solver (APBS) software was developed to solve the equations of continuum electrostatics for large biomolecular assemblages that has provided impact in the study of a broad range of chemical, biological, and biomedical applications. APBS addresses three key technology challenges for understanding solvation and electrostatics in biomedical applications: accurate and efficient models for biomolecular solvation and electrostatics, robust and scalable software for applying those theories to biomolecular systems, and mechanisms for sharing and analyzing biomolecular electrostatics data in the scientific community. To address new research applications and advancing computational capabilities, we have continually updated APBS and its suite of accompanying software since its release in 2001. In this manuscript, we discuss the models and capabilities that have recently been implemented within the APBS software package including: a Poisson-Boltzmann analytical and a semi-analytical solver, an optimized boundary element solver, a geometry-based geometric flow solvation model, a graph theory based algorithm for determining pKa values, and an improved web-based visualization tool for viewing electrostatics.
Brownian dynamic study of an enzyme metabolon in the TCA cycle: Substrate kinetics and channelingHuang, Y.M., G.A. Huber, N. Wang, S.D. Minteer, J.A. McCammonProtein Sci. in press (2017)    
Malate dehydrogenase (MDH) and citrate synthase (CS) are two pacemaking enzymes involved in the tricarboxylic acid (TCA) cycle. Oxaloacetate (OAA) molecules are the intermediate substrates that are transferred from the MDH to CS to carry out sequential catalysis. It is known that, to achieve a high flux of intermediate transport and reduce the probability of substrate leaking, a MDH-CS metabolon forms to enhance the OAA substrate channeling. In this study, we aim to understand the OAA channeling within possible MDH-CS metabolons that have different structural orientations in their complexes. Three MDH-CS metabolons from native bovine, wild-type porcine and recombinant sources, published in recent work, were selected to calculate OAA transfer efficiency by Brownian dynamics (BD) simulations and to study, through electrostatic potential calculations, a possible role of charges that drive the substrate channeling. Our results show that an electrostatic channel is formed in the metabolons of native bovine and recombinant porcine enzymes, which guides the oppositely-charged OAA molecules passing through the channel and enhances the transfer efficiency. However, the channeling probability in a suggested wild-type porcine metabolon conformation is reduced due to an extended diffusion length between the MDH and CS active sites, implying that the corresponding arrangements of MDH and CS result in the decrease of electrostatic steering between substrates and protein surface and then reduce the substrate transfer efficiency from one active site to another. This article is protected by copyright. All rights reserved.
Unique Hydrophobic Binding Sites Dominate Specificity of PhospholipasesMouchlis, V.D., Y. Chen, J.A. McCammon, E.A. DennisJ. Amer. Chem. Soc. in press (2018)    
Remarkable similarity in P. falciparum and P. vivax Geranylgeranyl Diphosphate Synthase (GGPPS) dynamics and its implication for anti-malarial drug design.Venkatramani, A., C.G. Ricci, E. Oldfield, J.A. McCammon.Chem. Biol. Drug Disc. in press (2018)    
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