A Multiscale computational framework for studying G-protein coupled receptors (GPCRs)


G-protein coupled receptors (GPCRs) play an important role in the physiology and in the pathophysiology of many serious diseases. They form the largest superfamily of drug targets. Since GPCRs are membrane bound and are highly dynamic, obtaining three dimensional structural information for GPCRs is a feat and it requires a confluence of various biophysical techniques that include computational methods. The crystal structure is a snapshot in the conformational ensemble that the receptor samples in the absence of any stimulant. We are developing multiscale simulation method suite, GPCRSimKit, that integrates coarse grain simulation method with fine grain techniques. The GPCRSimKit will enable simulation of the dynamics of GPCR conformational ensemble starting from the inactive crystal structures or refine homology models for drug design. The GPCRSimkit will allow calculation of the modulation of the potential energy landscape by full, partial, and inverse agonists. This platform of computational techniques, will lay a theoretical basis and play a crucial role as more crystal structures of GPCRs get published. 

Publications Related to this project:

• Vaidehi, N., et al 2002, Structure and Function prediction for G-Protein Coupled Receptors, Proc. Natl. Acad. Sci., USA, 99, 12622-12627.
• Bhattacharya S., Hall S.E., Li H., Vaidehi N., Ligand-stabilized conformational states of human beta(2) adrenergic receptor: insight into G-protein-coupled receptor activation. Biophys J. 2008, 94(6):2027-42.
• Bhattacharya, S., Hall, S.E. and Vaidehi N., 2008, Agonist induced conformational changes in bovine rhodopsin: Insight into activation of G-protein coupled receptors, J. Mol. Biol. 382, 539-555.
• Hall, S.E., Roberts, K., and Vaidehi, N., 2009, Position of helical kinks in membrane protein crystal structures and the accuracy of computational prediction, J. Mol. Graph. & Mod. 27, 944-950.
• Hall S.E.,  Mao, A. Nicolaidou, V., Finelli, M., Wise, E.L., Nedjai, B., Kanjanapangka, J., Harirchian, P., Chen, D., Selchau, V., Ribeiro, S., Schyler, S.,  Pease, J.E.,  Horuk R., and Vaidehi, N. 2009, Elucidation of binding sites of dual antagonists in the human chemokine receptors CCR2 and CCR5. Mol. Pharm. 75, 1325-1336.
• Vaidehi, N., Pease, J. and Horuk R., 2009, Modeling Small Molecule Compound Binding to G-Protein Coupled Receptors, Methods in Enzymology, 460, 263-288.
• Bhattacharya S, and Vaidehi N. 2010, Computational Mapping of the Conformational Transitions in Agonist Selective Pathways of a G-Protein Coupled Receptor, J Am Chem Soc. 132(14):5205-14.
• Bhattacharya et al 2010, Allosteric Antagonist Binding Sites in Class B GPCRs: Corticotropin Receptor 1, J Comput Aided Mol Des. 8, 659-74.
• Vaidehi, N., 2010, Dynamics and Flexibility of G-protein coupled receptor conformations and its relevance to drug design, Drug Discovery Today, 15, 951-957 – invited review. 
• Vaidehi N., and Kenakin T., 2010, Conformational Ensembles of Seven Transmembrane Receptors and their Relevance to Functional Selectivity, Curr. Opinion. Pharmacology, 10, 775-781- invited review.
• Lam AR, Bhattacharya S, Patel K, Hall SE, Mao A, Vaidehi N. 2011 Importance of receptor flexibility in binding of cyclam compounds to the chemokine receptor CXCR4 J Chem Inf Model. 24;51(1):139-47.