2020
DOI: 10.3390/ijms21165933
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How Do Molecular Dynamics Data Complement Static Structural Data of GPCRs

Abstract: G protein-coupled receptors (GPCRs) are implicated in nearly every physiological process in the human body and therefore represent an important drug targeting class. Advances in X-ray crystallography and cryo-electron microscopy (cryo-EM) have provided multiple static structures of GPCRs in complex with various signaling partners. However, GPCR functionality is largely determined by their flexibility and ability to transition between distinct structural conformations. Due to this dynamic nature, a static snaps… Show more

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Cited by 38 publications
(30 citation statements)
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References 196 publications
(233 reference statements)
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“…However, their proposed energy landscape is based on inferences drawn from cryo-EM data and does not take the inherently dynamic nature of the proteins into account 55 . Unlike X-ray crystallography and cryo-EM, MD simulations are able to provide detailed information on the dynamic behavior of proteins and other biomolecules 46, 47 . However, each computational or experimental technique has its own assumptions and limitations.…”
Section: Discussionmentioning
confidence: 99%
“…However, their proposed energy landscape is based on inferences drawn from cryo-EM data and does not take the inherently dynamic nature of the proteins into account 55 . Unlike X-ray crystallography and cryo-EM, MD simulations are able to provide detailed information on the dynamic behavior of proteins and other biomolecules 46, 47 . However, each computational or experimental technique has its own assumptions and limitations.…”
Section: Discussionmentioning
confidence: 99%
“…Therefore, alternative biophysical techniques including nuclear magnetic resonance (NMR) (reviewed in Ref. [58]), electron paramagnetic resonance (EPR) (reviewed in Refs [59,60]), and fluorescence spectroscopy (reviewed in Refs [61,62]) supported by molecular dynamics (MD) simulations (reviewed in Refs [63,64]) have been used in complementation to crystallographic and cryo-EM studies to analyze different conformational states of GPCRs and to determine their liganddependent energetics and rates of interconversion. Several NMR studies on the b 1 and b 2 adrenergic receptors (b 1 AR and b 2 AR) [65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80], the adenosine A 2A receptor (A 2A R) [81][82][83][84][85][86][87], the l-opioid receptor (lOR) [88,89], the leukotriene B 4 receptor 2 (BLT2R) [90], the a 1A adrenergic receptor (a 1A R) [91], the neurotensin receptor type 1 (NTSR1) [92], and the M 2 R [93,94] have shown that GPCRs are highly dynamic proteins that exist in an equilibrium between multiple functionally relevant conformational states.…”
Section: Ligand-dependent Conformational Dynamics Of the Intracellulamentioning
confidence: 99%
“…For instance, Flock et al provided a bioinformatics approach to determine a selectivity barcode (patterns of amino acids) of GPCR−G protein coupling [ 42 ]. More commonly, molecular dynamics (MD) simulations have been used to explore the conformational changes and free energy landscapes of GPCR–G protein interactions, ideally combined with complementary experiments [ 63 , 64 , 65 ]. However, conventional MD (cMD) simulations often suffer from insufficient sampling of GPCR–G protein interactions due to limited simulation timescales.…”
Section: Introductionmentioning
confidence: 99%