Fig. 2: Flexibility analysis of the GPCR core. | Nature Communications

Fig. 2: Flexibility analysis of the GPCR core.

From: Large scale investigation of GPCR molecular dynamics data uncovers allosteric sites and lateral gateways

Fig. 2: Flexibility analysis of the GPCR core.The alternative text for this image may have been generated using AI.

a Structural depiction of the TM6 outward movement and the residues used to measure the TM2-TM6 distance (i.e., class A, B1, C: 2 × 46 and 6 × 37, class F: 2 × 44 and 6 × 31) (left). Distribution plot of the TM2-TM6 distance for class A, B1, C and F for active states (i.e., GPCR structures bound to a G protein) and inactive states according to GPCRdb classification. Boxplots display the average (µ), standard deviation (σ) and sample size (n) for each group. The centre line in boxplots represents the median while the box boundaries extend from the first (25%) and third (75%) quartile, representing the interquartile range (IQR). Boxplot whiskers extend to 1.5 × IQR and outliers are represented as circles. Statistical significance was assessed by a two-sided Mann-Whitney U test (class A P = 3.2 × 10−92, class B1 P = 1.1 × 10−8, class C P = 0.83, class F P = 4.3 × 10−3). b Conformational flexibility in simulated systems of GPCR class A and B1. We monitored closed, intermediate and open states based on the TM2-TM6 distance during 3 × 500 ns. Bar plots show the results for 107 simulated apo GPCRs (top) and the corresponding systems in complex with antagonists, inverse agonists or NAMs, respectively (bottom). Values available in Supplementary Data 2. c, d Structural depiction of two case studies from our dataset, represented in their open (purple), intermediate (green) and closed (grey) conformations visited during one of its apo simulations replicates. The data for the adenosine A2A receptor (PDB id: 5UIG) are available with GPCRmd id: 773 [https://www.gpcrmd.org/view/773], trajectory id: 15597. The simulation data for the CC2 chemokine receptor (PDB id: 6GPX) are accessible via the GPCRmd id: 799 [https://www.gpcrmd.org/view/799], trajectory 15764. The measured TM2-TM6 distances are marked in red. e Estimation of the average breathing kinetics across the 107 GPCR system pairs selected in b. The transition timescales from the closed to intermediate state (left) and from the closed to the open state (right) for apo and complex systems are shown including the 95% confidence interval (ci), respectively. Source data are provided in the Source Data file.

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