How Do Molecular Dynamics Data Complement Static Structural Data of GPCRs

Torrens‐Fontanals, Mariona; Stępniewski, Tomasz Maciej; Aranda-García, David; Morales-Pastor, Adrián; Medel-Lacruz, Brian; Selent, Jana

doi:10.3390/ijms21165933

Cited by 40 publications

(33 citation statements)

References 200 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%

Differential Dynamic Behavior of Prefusion Spike Proteins of SARS Coronaviruses 1 and 2

Kumar

Ogden

Isu

et al. 2020

Preprint

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Within the last two decades, severe acute respiratory syndrome (SARS) coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) have caused two major outbreaks. For reasons yet to be fully understood the COVID-19 outbreak caused by SARS-CoV-2 has been significantly more widespread than the 2003 SARS epidemic caused by SARS-CoV-1, despite striking similarities between the two viruses. One of the most variable genes differentiating SARS-CoV-1 and SARS-CoV-2 is the S gene that encodes the spike glycoprotein. This protein mediates a crucial step in the infection, i.e., host cell recognition and viral entry, which starts with binding to the host cell angiotensin converting enzyme 2 (ACE2) protein for both viruses. Recent structural and functional studies have shed light on the differential binding behavior of the SARS-CoV-1 and SARS-CoV-2 spike proteins. In particular, cryogenic electron microscopy (cryo-EM) studies show that ACE2 binding is preceded by a large-scale conformational change in the spike protein to expose the receptor binding domain (RBD) to its binding partner. Unfortunately, these studies do not provide detailed information on the dynamics of this activation process. Here, we have used an extensive set of unbiased and biased microsecond-timescale all-atom molecular dynamics (MD) simulations of SARS-CoV-1 and SARS-CoV-2 spike protein ectodomains in explicit solvent to determine the differential behavior of spike protein activation in the two viruses. Our results based on nearly 50 microseconds of equilibrium and nonequilibrium MD simulations indicate that the active form of the SARS-CoV-2 spike protein is considerably more stable than the active SARS-CoV-1 spike protein. Unlike the active SARS-CoV-2 spike, the active SARS-CoV-1 spike spontaneously undergoes a large-scale conformational transition to a pseudo-inactive state, which occurs in part due to interactions between the N-terminal domain (NTD) and RBD that are absent in the SARS-CoV-2 spike protein. Steered MD (SMD) simulations indicate that the energy barriers between active and inactive states are comparatively lower for the SARS-CoV-1 spike protein. Based on these results, we hypothesize that the greater propensity of the SARS-CoV-2 spike protein to remain in the active conformation contributes to the higher transmissibility of SARS-CoV-2 in comparison to SARS-CoV-1. These results strongly suggest that the differential binding behavior of the active SARS-CoV-1 and 2 spike proteins is not merely due to differences in their RBDs as other domains of the spike protein such as the NTD could play a crucial role in the effective binding process, which involves the prebinding activation. Therefore, our hypothesis predicts that mutations in regions such as the NTD, which is not directly involved in binding, may lead to a change in the effective binding behavior of the coronavirus.

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Section: Discussionmentioning

confidence: 99%

Differential Dynamic Behavior of Prefusion Spike Proteins of SARS Coronaviruses 1 and 2

Kumar

Ogden

Isu

et al. 2020

Preprint

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“…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%

The role of structural dynamics in GPCR‐mediated signaling

Hilger

2021

The FEBS Journal

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G protein-coupled receptors (GPCRs) play critical roles in the regulation of human physiology in response to a wide array of different extracellular stimuli and thus represent one of the largest groups of therapeutic drug targets. Recent advances in the structural characterization of GPCRs in different conformations and in complex with G proteins and arrestins have provided important insights into the mechanism and function of GPCRs. However, in order to truly understand the molecular basis of the functional versatility of GPCRs, the structural snapshots obtained by X-ray crystallography or cryo-EM need to be complimented with information about the conformational dynamics of receptors and their signaling complexes. In the last decade, a combination of biophysical approaches and computational studies has been utilized to examine the molecular motions of GPCRs and their transducer complexes and how they are regulated by ligands of different efficacy and bias. These studies revealed that GPCRs are highly dynamic allosteric proteins that can sample multiple conformational states. Ligands with distinct signaling profiles not only impact the conformational landscape of GPCRs but also of the receptor-engaged G proteins and arrestins. The conformational dynamics of GPCRs and their signaling complexes and the ligand-dependent bias sampling of distinct functional states are important underlying principles behind the complex signaling behavior of GPCRs.

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“…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%

Specific Engineered G Protein Coupling to Histamine Receptors Revealed from Cellular Assay Experiments and Accelerated Molecular Dynamics Simulations

Höring

Conrad

Söldner

et al. 2021

IJMS

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G protein-coupled receptors (GPCRs) are targets of extracellular stimuli and hence occupy a key position in drug discovery. By specific and not yet fully elucidated coupling profiles with α subunits of distinct G protein families, they regulate cellular responses. The histamine H2 and H4 receptors (H2R and H4R) are prominent members of Gs- and Gi-coupled GPCRs. Nevertheless, promiscuous G protein and selective Gi signaling have been reported for the H2R and H4R, respectively, the molecular mechanism of which remained unclear. Using a combination of cellular experimental assays and Gaussian accelerated molecular dynamics (GaMD) simulations, we investigated the coupling profiles of the H2R and H4R to engineered mini-G proteins (mG). We obtained coupling profiles of the mGs, mGsi, or mGsq proteins to the H2R and H4R from the mini-G protein recruitment assays using HEK293T cells. Compared to H2R–mGs expressing cells, histamine responses were weaker (pEC50, Emax) for H2R–mGsi and –mGsq. By contrast, the H4R selectively bound to mGsi. Similarly, in all-atom GaMD simulations, we observed a preferential binding of H2R to mGs and H4R to mGsi revealed by the structural flexibility and free energy landscapes of the complexes. Although the mG α5 helices were consistently located within the HR binding cavity, alternative binding orientations were detected in the complexes. Due to the specific residue interactions, all mG α5 helices of the H2R complexes adopted the Gs-like orientation toward the receptor transmembrane (TM) 6 domain, whereas in H4R complexes, only mGsi was in the Gi-like orientation toward TM2, which was in agreement with Gs- and Gi-coupled GPCRs structures resolved by X-ray/cryo-EM. These cellular and molecular insights support (patho)physiological profiles of the histamine receptors, especially the hitherto little studied H2R function in the brain, as well as of the pharmacological potential of H4R selective drugs.

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How Do Molecular Dynamics Data Complement Static Structural Data of GPCRs

Cited by 40 publications

References 200 publications

Differential Dynamic Behavior of Prefusion Spike Proteins of SARS Coronaviruses 1 and 2

Differential Dynamic Behavior of Prefusion Spike Proteins of SARS Coronaviruses 1 and 2

The role of structural dynamics in GPCR‐mediated signaling

Specific Engineered G Protein Coupling to Histamine Receptors Revealed from Cellular Assay Experiments and Accelerated Molecular Dynamics Simulations

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