Structural Biology and Molecular Biophysics

Hidden GPCR structural transitions addressed by multiple walker supervised molecular dynamics (mwSuMD)

Giuseppe Deganutti author has email address
Ludovico Pipitò
Roxana M Rujan
Tal Weizmann
Peter Griffin
Antonella Ciancetta
Stefano Moro
Christopher A Reynolds author has email address

Centre for Health and Life Sciences, Coventry University, Coventry, UK
Dipartimento di Scienze Chimiche, Farmaceutiche ed Agrarie, University of Ferrara, Ferrara, Italy
Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, University of Padua via Marzolo 5, Padova, Italy
School of Life Sciences, University of Essex, Colchester, UK

https://doi.org/10.7554/eLife.96513.2

Open access
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Figures and data

AVP SuMD and mwSuMD binding simulations to V₂R (100 ps time windows).
For each set of settings (a-d) the RMSD of AVP Cα atoms to the cryo-EM structure 7DW9 is reported during the time course of each SuMD (a) or mwSuMD (b-d) replica alongside the RMSD values distribution and the snapshot corresponding to the lowest RMSD values (AVP from the cryo-EM structure 7DW9 is in a cyan stick representation, while AVP from simulations is in a tan stick representation). A complete description of the simulation settings is reported in Table S1 and the Methods section. The dashed red line indicates the AVP RMSD during a classic (unsupervised) equilibrium MD simulation of the X-ray AVP:V₂R complex (Figure S2).

mwSuMD simulation of PF06882961 binding to GLP-1R and receptor activation.
Each panel reports the root mean square deviation (RMSD) to the position of the ligand in the active state (top panel) or a GLP-1R structural element, over the time course (all but ECL3 converging to the active state). ECD: extracellular domain; TM: transmembrane helix; ECL: extracellular loop. The mwSuMD simulation was performed with four different settings over 1 microsecond in total. The red dashed lines show the initial RMSD value for reference.

GLP-1R key structural motifs during mwSuMD GLP-1R activation.
a) RMSD to the active state GLP-1R (7LCI) of the residues forming the central polar network (magenta) and TM6 kink (orange) during mwSuMD of receptor activation; at the end of the simulations minimum values were reached (dashed square). b) The position of the polar network within the core of TMD (left-hand panel) and comparison between inactive, active and mwSuMD final states for the side chains of the residues forming of the polar network; c) The position of the TM6 kink (right-hand panel) and comparison between inactive, active and mwSuMD final states for the side chains of the residues forming the TM6 kink.

GLP-1R activation and G_s binding.
a-d) sequence of simulated events during the mwSuMD G_s:GLP-1R simulations. e) RMSD of G_sα to the experimental GLP-1R:G_s complex (PDB 7LCJ) during three mwSuMD replicas; the RMSD to the experiential bound conformation (7LCJ) during the second part of Replica2 (red dashed line) is reported for each G_s subunit. RMSDs were computed on G_α residues 11 to 43 and 205 to 394 to the experimental structure 7LCI after superimposition on GLP-1R residues 140-240 Cα atoms. f) RMSD of the αG-α4 loop (purple), the distance between K342^6.31 and D323^Gα (salmon), and the distance between GDP and D295^Gα (green) during G_s binding, AHD opening and GDP dissociation; g) and h) comparison between states extracted from before and after AHD opening. Before AHD opening (a), GLP-1R ICL3 interacted with D323^Gα and D295 ^Gα interacted with GDP; after AHD opening (b) and αG-α4 loop reorganization (curved red arrow), αG and D295 ^Gα moved away from GDP (straight red arrow), destabilizing its binding to G_s.

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