LITiCon: a discrete conformational sampling computational method for mapping various functionally selective conformational states of transmembrane helical proteins.

G-Protein-coupled receptors (GPCRs) are seven helical transmembrane proteins that mediate cell signaling thereby controlling many important physiological and pathological functions. GPCRs get activated upon ligand binding and trigger the signal transduction process. GPCRs exist in multiple inactive and active conformations, and there is a finite population of the active and inactive states even in the ligand-free condition. An understanding of the nature of the conformational ensemble sampled by GPCRs and the atomic level mechanism of the conformational transitions require a combination of computational methods and experimental techniques. We have developed a coarse grained discrete conformational sampling computational method called "LITiCon" to map the conformational ensemble sampled by GPCRs in the presence and absence of ligands. The LITiCon method can also be used to predict functional selective conformational states starting from the inactive state of the receptor. LITiCon has been applied to map the conformational ensemble of β2-adrenergic receptor, a class A GPCR. We have shown that β2-adrenergic receptor samples a larger conformational space in the ligand-free state and that different ligands select and stabilize conformations from this ensemble. In this review we describe the LITiCon method in detail and elucidate the uses and pitfalls of this method.

[1]  Jianping Lin,et al.  Allosteric antagonist binding sites in class B GPCRs: corticotropin receptor 1 , 2010, J. Comput. Aided Mol. Des..

[2]  Kevin Patel,et al.  Importance of Receptor Flexibility in Binding of Cyclam Compounds to the Chemokine Receptor CXCR4 , 2011, J. Chem. Inf. Model..

[3]  Adrian A Canutescu,et al.  Access the most recent version at doi: 10.1110/ps.03154503 References , 2003 .

[4]  G. Zamanakos A fast and accurate analytical method for the computation of solvent effects in molecular simulations , 2002 .

[5]  Nagarajan Vaidehi,et al.  Ligand-stabilized conformational states of human beta(2) adrenergic receptor: insight into G-protein-coupled receptor activation. , 2008, Biophysical journal.

[6]  H. Kikkawa,et al.  Differential contribution of two serine residues of wild type and constitutively active β2‐adrenoceptors to the interaction with β2‐selective agonists , 1997, British journal of pharmacology.

[7]  Nagarajan Vaidehi,et al.  Agonist-induced conformational changes in bovine rhodopsin: insight into activation of G-protein-coupled receptors. , 2008, Journal of molecular biology.

[8]  J. Thornton,et al.  Satisfying hydrogen bonding potential in proteins. , 1994, Journal of molecular biology.

[9]  Yang Xiang,et al.  Sequential binding of agonists to the beta2 adrenoceptor. Kinetic evidence for intermediate conformational states. , 2004, The Journal of biological chemistry.

[10]  Christy F. Landes,et al.  Structural landscape of the isolated ligand binding domain of single AMPA receptors , 2011, Nature chemical biology.

[11]  S. Rasmussen,et al.  Structure of a nanobody-stabilized active state of the β2 adrenoceptor , 2010, Nature.

[12]  Nagarajan Vaidehi,et al.  Computational mapping of the conformational transitions in agonist selective pathways of a G-protein coupled receptor. , 2010, Journal of the American Chemical Society.

[13]  T. Kenakin,et al.  The role of conformational ensembles of seven transmembrane receptors in functional selectivity. , 2010, Current opinion in pharmacology.

[14]  R. Stevens,et al.  Structure of an Agonist-Bound Human A2A Adenosine Receptor , 2011, Science.

[15]  N. Vaidehi,et al.  Structural insights into conformational stability of wild-type and mutant beta1-adrenergic receptor. , 2010, Biophysical journal.

[16]  Xavier Deupi,et al.  Probing the β2 Adrenoceptor Binding Site with Catechol Reveals Differences in Binding and Activation by Agonists and Partial Agonists* , 2005, Journal of Biological Chemistry.

[17]  Christopher G. Tate,et al.  The structural basis for agonist and partial agonist action on a β1-adrenergic receptor , 2010, Nature.

[18]  R. Mailman,et al.  Ligand functional selectivity advances our understanding of drug mechanisms and drug discovery , 2009, Neuropsychopharmacology.

[19]  Nagarajan Vaidehi,et al.  The role of conformational ensembles in ligand recognition in G-protein coupled receptors. , 2011, Journal of the American Chemical Society.

[20]  Nagarajan Vaidehi,et al.  Dynamics and flexibility of G-protein-coupled receptor conformations and their relevance to drug design. , 2010, Drug discovery today.

[21]  Terry Kenakin,et al.  Collateral efficacy in drug discovery: taking advantage of the good (allosteric) nature of 7TM receptors. , 2007, Trends in pharmacological sciences.