Fig. 6: Conformational free energy landscape of S4 movement in wild-type, R531Q, and R528Q hERG channels.
From: Voltage sensor conformations induced by LQTS-associated mutations in hERG potassium channels
One-dimensional potential of mean force (PMF) profiles for the monomer transmembrane domains of wild-type WT (a), R531Q (b), and R528Q (c) hERG variants, obtained via umbrella sampling based on steered molecular dynamics trajectories along a defined reaction coordinate. The profiles depict free energy minima along the collective displacement of residues 525, 528, and 531 (used as collective variables) as the S4 transitions from the intermediate I to the up conformation. Free-energy minima are highlighted by triangles in red. d Schematic representations of the VSD topology and associated charge interactions in the down, intermediate I, intermediate II, and up states. Negatively charged residues (in red) within the S1 to S3 helices and positively charged residues (in blue) within the S4 are highlighted. The intermediate I conformation differs between the WT and the R531Q or R528Q mutants. The intermediate II is most stable in the R528Q mutant.
