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Conformational and Thermodynamic Landscape of GPCR Activation from Theory and Computation

Dong, Sijia S. and Goddard, William A., III and Abrol, Ravinder (2016) Conformational and Thermodynamic Landscape of GPCR Activation from Theory and Computation. Biophysical Journal, 110 (12). pp. 2618-2629. ISSN 0006-3495. PMCID PMC4919603. doi:10.1016/j.bpj.2016.04.028.

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We present a hybrid computational methodology to predict multiple energetically accessible conformations for G protein-coupled receptors (GPCRs) that might play a role in binding to ligands and different signaling partners. To our knowledge, this method, termed ActiveGEnSeMBLE, enables the first quantitative energy profile for GPCR activation that is consistent with the qualitative profile deduced from experiments. ActiveGEnSeMBLE starts with a systematic coarse grid sampling of helix tilts/rotations (∼13 trillion transmembrane-domain conformations) and selects the conformational landscape based on energy. This profile identifies multiple potential active-state energy wells, with the TM3–TM6 intracellular distance as an approximate activation coordinate. These energy wells are then sampled locally using a finer grid to find locally minimized conformation in each energy well. We validate this strategy using the inactive and active experimental structures of β_2 adrenergic receptor (hβ_2AR) and M2 muscarinic acetylcholine receptor. Structures of membrane-embedded hβ_2AR along its activation coordinate are subjected to molecular-dynamics simulations for relaxation and interaction energy analysis to generate a quantitative energy landscape for hβ_2AR activation. This landscape reveals several metastable states along this coordinate, indicating that for hβ_2AR, the agonist alone is not enough to stabilize the active state and that the G protein is necessary, consistent with experimental observations. The method’s application to somatostatin receptor SSTR5 (no experimental structure available) shows that to predict an active conformation it is better to start from an inactive structure template based on a close homolog than to start from an active template based on a distant homolog. The energy landscape for hSSTR5 activation is consistent with hβ_2AR in the role of the G protein. These results demonstrate the utility of the ActiveGEnSeMBLE method for predicting multiple conformations along the pathways for activating GPCRs and the corresponding energy landscapes, thereby providing detailed structural insights into the initial molecular events of GPCR function that are not easily accessible by experiments.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Dong, Sijia S.0000-0002-5811-9333
Goddard, William A., III0000-0003-0097-5716
Abrol, Ravinder0000-0001-7333-6793
Additional Information:© 2016 Biophysical Society. Received 29 January 2016, Accepted 13 April 2016, Available online 21 June 2016. We thank Dr. Soo-Kyung Kim, Adam Griffith, and Dr. Vaclav Cvicek for helpful discussions. Partial support was provided by the NSF (EFRI-1332411), the GIST-Caltech Project, the NIH (R01AI040567), and donors to the Materials and Process Simulation Center at California Institute of Technology. Partial support for R.A. was provided from startup funds from Cedars-Sinai Medical Center. Author Contributions: S.S.D. designed and performed research, and wrote the manuscript. W.A.G. and R.A. designed research and wrote the manuscript.
Funding AgencyGrant Number
Cedars-Sinai Medical CenterUNSPECIFIED
Issue or Number:12
PubMed Central ID:PMC4919603
Record Number:CaltechAUTHORS:20160622-080207374
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Official Citation:Sijia S. Dong, William A. Goddard III, Ravinder Abrol, Conformational and Thermodynamic Landscape of GPCR Activation from Theory and Computation, Biophysical Journal, Volume 110, Issue 12, 21 June 2016, Pages 2618-2629, ISSN 0006-3495, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:68561
Deposited By: Tony Diaz
Deposited On:22 Jun 2016 20:06
Last Modified:11 Nov 2021 04:01

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