Fig. 3: Mutation of distant, coevolving residue positions induces dynamic structural changes in the GAFa domain of PDE5.
From: Coevolving residues distant from the ligand binding site are involved in GAF domain function
A Cartoon representation of GAFa domain (WT, left panel; L267A mutant, middle panel; and F295A mutant, right panel) dynamics across the 1000 ns-long MD simulation runs captured using a composite image of snapshots that are 200 ns apart. The ligand is shown as blue carbon sticks, and positions 267 and 295 are shown as green carbon sticks in each complex. B Graphs showing root mean squared deviation (RMSD) measurements of the apo and holo GAFa domains (WT and mutants) across the 1000 ns-long MD simulation runs. C Schematic (left panel) and graphs showing root mean square fluctuation (RMSF) measurements of the apo and holo GAFa domains (WT and mutants) across the 1000 ns-long MD simulation runs (right panel). D Graphs showing radius of gyration (Rg) values of the apo and holo GAFa domains (WT and mutants) across the 1000 ns-long MD simulation runs. E Schematic highlighting residues L267 and F295 (left panel) and graphs showing center-of-mass distance between amino acid positions 267 and 295 in the apo and holo GAFa domains (WT and mutants; right panel). Note how the hydrophobic interaction is disrupted in the F295A mutant domain as is evident from the increased distance between the two positions, as opposed to the WT and L267A mutant GAFa domains that maintained the distance across the 1000 ns-long MD simulation runs. F Schematic highlighting ligand (cGMP) surface (left panel) and graph showing solvent-accessible surface area (SASA) of cGMP across the 1000 ns-long MD simulation runs of the holo GAFa domain (WT and mutants; right panel). Outsets, frequency distribution of ligand SASA across the 1000 ns-long MD simulation runs of each complex. G Graphs showing dynamic cross-correlation (DCC) values of residue positions 267 (top panel) and 295 (bottom panel) in the apo and holo GAFa domain (WT and mutants) obtained from the 1000 ns-long MD simulation runs. Vertical dotted lines indicate residue 267 in graphs in the top panel and residue 295 in graphs in the bottom panel, while horizontal dotted lines indicate DCC values of 0.5 and −0.5.
