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.