MD Simulations and Conformational Sampling of Monomeric and Dimeric GPCRs

Abstract

G protein-coupled receptors (GPCRs) constitute the largest family of membrane-bound receptors with more than 800 members encoded by 351 genes in humans. It has been estimated that more than the 50% of clinically available drugs act on GPCRs, with an amount of about 400, 50 and 25 druggable proteins for the class A, B and C, respectively. Furthermore, Class A GPCRs, with approximately 25% of marketed small drugs, represents the most attractive pharmaceutical class so far identified. The recent availability of high-resolution 3-dimensional structures of some GPCRs supports the notion that GPCRs are dynamically versatile, and their functions can be modulated by several factors. In this scenario, molecular dynamics (MD) simulations techniques appear to be crucial when studying GPCR flexibility associated to functioning and ligand recognition. In this project we have focused on two aspects of GPCR functioning, which are gaining a considerable interest, namely dimerization and membrane composition. In particular, we have studied the effect of different dimer interfaces, and the effect of cholesterol concentration on the flexibility of two pharmaceutically relevant GPCRs, the 5-HT2A and the mGluR2 receptors. Herein I report several methodological tools useful in the study of the effects of the aforementioned issues on GPCRs flexibility, and we propose that the chosen MD simulation conditions strongly impact the results carried out by the MD toolbox. This has to be taken into account when using these models for further computational studies, such as in silico screening or docking purposes.