Reshaping the dynamics of follicle-stimulant hormone receptor models in polyunsaturated lipid bilayers. Calculation of conformational free energy landscapes of α-helical domains from all-atom MD simulations

Abstract

AbstractG-coupled-protein receptors (GPCR) are conspicuous target molecules for novel therapeutic drugs due to their role as mediators of cellular responses. Structural biology of GPCR revealed that intracellular signaling stimulated by extracellular ligands involves subtle conformational changes of the receptor during activation. Nonetheless, transitions among intermediates evolve in an intricate and rough free energy landscape of the conformational space. Experimental evidence suggests that the membrane environment is an active modulator of the receptor dynamics; therefore, the lipid composition may facilitate conformational transitions towards productive signaling states. In this study, we setup molecular dynamics simulations to examine the conformational dynamics of the transmembrane domains, in the context of a membrane of polyunsaturated phospholipid molecules, for a homology model of the human follicle-stimulating-hormone receptor (FSHR) and the crystal structure of the Lumi intermediate of the squid rhodopsin (LSRh). The conformational dynamics of the α−helical domains of LSRh was consistent with interactions stabilizing the crystal structure, which remained well preserved in the membrane environment. In contrast, conformations in the FSHR model evolved towards stable states in the membrane environment. To assess the relevance of the conformational dynamics in the FSHR model, dihedral restraints were imposed for the helical domains on top of the force field. This strategy was implemented to reoptimize the interhelical interactions probably overlooked in the modeling process. The conformational dynamics in the helical domains was evaluated by the TM-score, contact maps, principal components analysis of Cα atoms at the helical domains, and projections of the conformational free energy on principal components. The roughness of the conformational landscape in the FSHR model without dihedral restraints, suggested that alternative interhelical conformational states were populated, whereas imposing restraints led to a dominant conformational state. Template-based models of GPCR, with reoptimized interhelical interactions using dihedral restraints, may enhance the identification of binding sites for potential therapeutic drugs.