Free Energy Landscape of G-protein Coupled Receptors, Explored by Accelerated Molecular Dynamics

Overview

Journal Phys Chem Chem Phys

Publisher Royal Society of Chemistry

Specialties Biophysics
Chemistry

Date 2014 Jan 22

PMID 24445284

Citations 35

Authors

Yinglong Miao

Sara E Nichols

J Andrew McCammon

Affiliations

Soon will be listed here.

Abstract

G-protein coupled receptors (GPCRs) mediate cellular responses to various hormones and neurotransmitters and are important targets for treating a wide spectrum of diseases. They are known to adopt multiple conformational states (e.g., inactive, intermediate and active) during their modulation of various cell signaling pathways. Here, the free energy landscape of GPCRs is explored using accelerated molecular dynamics (aMD) simulations as demonstrated on the M2 muscarinic receptor, a key GPCR that regulates human heart rate and contractile forces of cardiomyocytes. Free energy profiles of important structural motifs that undergo conformational transitions upon GPCR activation and allosteric signaling are analyzed in detail, including the Arg(3.50)-Glu(6.30) ionic lock, the Trp(6.48) toggle switch and the hydrogen interactions between Tyr(5.58)-Tyr(7.53).

Citing Articles

Coevolution-Driven Method for Efficiently Simulating Conformational Changes in Proteins Reveals Molecular Details of Ligand Effects in the β2AR Receptor.

Mitrovic D, Chen Y, Marciniak A, Delemotte L J Phys Chem B. 2023; 127(46):9891-9904.

PMID: 37947090 PMC: 10683026. DOI: 10.1021/acs.jpcb.3c04897.

Using accelerated molecular dynamics simulation to shed light on the mechanism of activation/deactivation upon mutations for CCR5.

Zhang F, Yuan Y, Li H, Shen L, Guo Y, Wen Z RSC Adv. 2022; 8(66):37855-37865.

PMID: 35558583 PMC: 9089863. DOI: 10.1039/c8ra07686c.

Mechanistic insight into the impact of a bivalent ligand on the structure and dynamics of a GPCR oligomer.

Mansoor S, Kayik G, Durdagi S, Sensoy O Comput Struct Biotechnol J. 2022; 20:925-936.

PMID: 35242285 PMC: 8861583. DOI: 10.1016/j.csbj.2022.01.016.

Development of enhanced conformational sampling methods to probe the activation landscape of GPCRs.

Abrol R, Serrano E, Santiago L Adv Protein Chem Struct Biol. 2022; 128:325-359.

PMID: 35034722 PMC: 11476118. DOI: 10.1016/bs.apcsb.2021.11.001.

Binding Analysis Using Accelerated Molecular Dynamics Simulations and Future Perspectives.

Pawnikar S, Bhattarai A, Wang J, Miao Y Adv Appl Bioinform Chem. 2022; 15:1-19.

PMID: 35023931 PMC: 8747661. DOI: 10.2147/AABC.S247950.

References

Hamelberg D, Mongan J, McCammon J . Accelerated molecular dynamics: a promising and efficient simulation method for biomolecules. J Chem Phys. 2004; 120(24):11919-29. DOI: 10.1063/1.1755656. View

Vanni S, Rothlisberger U . A closer look into G protein coupled receptor activation: X-ray crystallography and long-scale molecular dynamics simulations. Curr Med Chem. 2012; 19(8):1135-45. DOI: 10.2174/092986712799320493. View

Deupi X, Kobilka B . Energy landscapes as a tool to integrate GPCR structure, dynamics, and function. Physiology (Bethesda). 2010; 25(5):293-303. PMC: 3056154. DOI: 10.1152/physiol.00002.2010. View

Dror R, Arlow D, Borhani D, Jensen M, Piana S, Shaw D . Identification of two distinct inactive conformations of the beta2-adrenergic receptor reconciles structural and biochemical observations. Proc Natl Acad Sci U S A. 2009; 106(12):4689-94. PMC: 2650503. DOI: 10.1073/pnas.0811065106. View

Bastug T, Kuyucak S . Molecular dynamics simulations of membrane proteins. Biophys Rev. 2017; 4(3):271-282. PMC: 5418402. DOI: 10.1007/s12551-012-0084-9. View

Shimamura T, Shiroishi M, Weyand S, Tsujimoto H, Winter G, Katritch V . Structure of the human histamine H1 receptor complex with doxepin. Nature. 2011; 475(7354):65-70. PMC: 3131495. DOI: 10.1038/nature10236. View

Niesen M, Bhattacharya S, Vaidehi N . The role of conformational ensembles in ligand recognition in G-protein coupled receptors. J Am Chem Soc. 2011; 133(33):13197-204. DOI: 10.1021/ja205313h. View

Pierce L, Salomon-Ferrer R, de Oliveira C, McCammon J, Walker R . Routine Access to Millisecond Time Scale Events with Accelerated Molecular Dynamics. J Chem Theory Comput. 2012; 8(9):2997-3002. PMC: 3438784. DOI: 10.1021/ct300284c. View

Bucher D, Grant B, Markwick P, McCammon J . Accessing a hidden conformation of the maltose binding protein using accelerated molecular dynamics. PLoS Comput Biol. 2011; 7(4):e1002034. PMC: 3080849. DOI: 10.1371/journal.pcbi.1002034. View

10.

de Oliveira C, Hamelberg D, McCammon J . Estimating kinetic rates from accelerated molecular dynamics simulations: alanine dipeptide in explicit solvent as a case study. J Chem Phys. 2007; 127(17):175105. DOI: 10.1063/1.2794763. View

11.

Arrar M, de Oliveira C, Fajer M, Sinko W, McCammon J . w-REXAMD: A Hamiltonian Replica Exchange Approach to Improve Free Energy Calculations for Systems with Kinetically Trapped Conformations. J Chem Theory Comput. 2013; 9(1):18-23. PMC: 3541756. DOI: 10.1021/ct300896h. View

12.

Park J, Scheerer P, Hofmann K, Choe H, Ernst O . Crystal structure of the ligand-free G-protein-coupled receptor opsin. Nature. 2008; 454(7201):183-7. DOI: 10.1038/nature07063. View

13.

Lappano R, Maggiolini M . G protein-coupled receptors: novel targets for drug discovery in cancer. Nat Rev Drug Discov. 2011; 10(1):47-60. DOI: 10.1038/nrd3320. View

14.

Trzesniak D, Kunz A, van Gunsteren W . A comparison of methods to compute the potential of mean force. Chemphyschem. 2006; 8(1):162-9. DOI: 10.1002/cphc.200600527. View

15.

Vanommeslaeghe K, Hatcher E, Acharya C, Kundu S, Zhong S, Shim J . CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J Comput Chem. 2009; 31(4):671-90. PMC: 2888302. DOI: 10.1002/jcc.21367. View

16.

Wereszczynski J, McCammon J . Nucleotide-dependent mechanism of Get3 as elucidated from free energy calculations. Proc Natl Acad Sci U S A. 2012; 109(20):7759-64. PMC: 3356667. DOI: 10.1073/pnas.1117441109. View

17.

Wang Y, Harrison C, Schulten K, McCammon J . Implementation of Accelerated Molecular Dynamics in NAMD. Comput Sci Discov. 2011; 4(1). PMC: 3115733. DOI: 10.1088/1749-4699/4/1/015002. View

18.

Wang Y, Markwick P, de Oliveira C, McCammon J . Enhanced Lipid Diffusion and Mixing in Accelerated Molecular Dynamics. J Chem Theory Comput. 2011; 7(10):3199-3207. PMC: 3191728. DOI: 10.1021/ct200430c. View

19.

Rasmussen S, DeVree B, Zou Y, Kruse A, Chung K, Kobilka T . Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature. 2011; 477(7366):549-55. PMC: 3184188. DOI: 10.1038/nature10361. View

20.

Phillips J, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E . Scalable molecular dynamics with NAMD. J Comput Chem. 2005; 26(16):1781-802. PMC: 2486339. DOI: 10.1002/jcc.20289. View