Fig. 6: Metadynamics simulation suggests the presence of a metastable binding pocket for KSI-6666 in S1PR1. | Nature Communications

Fig. 6: Metadynamics simulation suggests the presence of a metastable binding pocket for KSI-6666 in S1PR1.

From: Pseudoirreversible inhibition elicits persistent efficacy of a sphingosine 1-phosphate receptor 1 antagonist

Fig. 6

a Plot of the distance from Met124 (γ-carbon atom) to the carbon atom of the CF3– group on the distal benzene ring of (R)-KSI-6666 against the distance from Met124 to the carboxylic acid (O1 atom) of (R)-KSI-6666 in MetaD snapshots, and corresponding plot of Val124 mutant. Snapshots (n = 1000) were selected every 1 ns from ten independent 100-ns MetaD simulations for each form of S1PR1. The area where both distances were <25 Å is enlarged in the right-hand figure. The frequency of poses assigned to gate A (distance from γ-carbon atom to the carbon atom of the CF3– group: 2.5–7.8 Å; distance from γ-carbon atom to the O1 atom: 10–15 Å) and gate B (distance from γ-carbon atom to the carbon atom of the CF3– group: 7.8–12.5 Å; distance from γ-carbon atom to the O1 atom: 7.5–12.5 Å) is shown for the wild-type (blue) and Val124 mutant (red) proteins. b Time-dependent changes in the distance between the carbon atom of the CF3– group of (R)-KSI-6666 and the γ-carbon atom of Met124 for wild-type or Val124 for M124V mutant of S1PR1. The results of all runs are shown in the upper figures. The results of runs in which the binding of (R)-KSI-6666 lasted for at least 100 ns are extracted in the lower figures. c The locations of the “deep pocket” and the “Met pocket” in S1PR1. The 100 snapshots per run structures of (R)-KSI-6666 (every 1 ns in 100-ns simulations) from Run 7 and 10 were picked up together and randomly clustered into two groups based on RMSD. These two groups corresponded to structures belonging to the deep pocket (gate A) and Met pocket (gate B). The stick model illustrates the average position of (R)-KSI-6666 in each pocket. The figures below offer an enlarged view of each pocket, and the line model indicates all structures of (R)-KSI-6666 positioned in each pocket. Met124 is shown in CPK style and the boundaries of the cell membrane are shown by white grids. Source data are provided as a Source Data file.

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