TY - JOUR
T1 - Putative active states of a prototypic g-protein-coupled receptor from biased molecular dynamics.
AU - Provasi, Davide
AU - Filizola, Marta
N1 - Funding Information:
This work was supported by National Institutes of Health grant No. DA020032 and No. DA026434 from the National Institute on Drug Abuse. The computations were supported in part by the National Science Foundation through TeraGrid advanced computing resources provided by TeraGrid Resource Allocations Committee program No. MCB080077.
PY - 2010/5/19
Y1 - 2010/5/19
N2 - A major current focus of structural work on G-protein-coupled receptors (GPCRs) pertains to the investigation of their active states. However, for virtually all GPCRs, active agonist-bound intermediate states have been difficult to characterize experimentally owing to their higher conformational flexibility, and thus intrinsic instability, as compared to inactive inverse agonist-bound states. In this work, we explored possible activation pathways of the prototypic GPCR bovine rhodopsin by means of biased molecular dynamics simulations. Specifically, we used an explicit atomistic representation of the receptor and its environment, and sampled the conformational transition from the crystal structure of a photoactivated deprotonated state of rhodopsin to the low pH crystal structure of opsin in the presence of 11-trans-retinal, using adiabatic biased molecular dynamics simulations. We then reconstructed the system free-energy landscape along the predetermined transition trajectories using a path collective variable approach based on metadynamics. Our results suggest that the two experimental endpoints of rhodopsin/opsin are connected by at least two different pathways, and that the conformational transition is populated by at least four metastable states of the receptor, characterized by a different amplitude of the outward movement of transmembrane helix 6.
AB - A major current focus of structural work on G-protein-coupled receptors (GPCRs) pertains to the investigation of their active states. However, for virtually all GPCRs, active agonist-bound intermediate states have been difficult to characterize experimentally owing to their higher conformational flexibility, and thus intrinsic instability, as compared to inactive inverse agonist-bound states. In this work, we explored possible activation pathways of the prototypic GPCR bovine rhodopsin by means of biased molecular dynamics simulations. Specifically, we used an explicit atomistic representation of the receptor and its environment, and sampled the conformational transition from the crystal structure of a photoactivated deprotonated state of rhodopsin to the low pH crystal structure of opsin in the presence of 11-trans-retinal, using adiabatic biased molecular dynamics simulations. We then reconstructed the system free-energy landscape along the predetermined transition trajectories using a path collective variable approach based on metadynamics. Our results suggest that the two experimental endpoints of rhodopsin/opsin are connected by at least two different pathways, and that the conformational transition is populated by at least four metastable states of the receptor, characterized by a different amplitude of the outward movement of transmembrane helix 6.
UR - http://www.scopus.com/inward/record.url?scp=77956638608&partnerID=8YFLogxK
U2 - 10.1016/j.bpj.2010.01.047
DO - 10.1016/j.bpj.2010.01.047
M3 - Article
C2 - 20483344
AN - SCOPUS:77956638608
SN - 0006-3495
VL - 98
SP - 2347
EP - 2355
JO - Biophysical Journal
JF - Biophysical Journal
IS - 10
ER -