Fig. 4: MD simulation of THCV binding to TRPV6.

a, b THCV binding to site 1 with the tricyclic ring oriented towards the central pore (forward orientation, a) and towards the membrane (backward orientation, b). Cryo-EM model of protein is shown as green (subunit A) and pink (subunit B) cartoon, while THCV is shown as yellow sticks. Distributions of the center of THCV molecule modeled in the forward and backward orientations are shown as blue and pink surfaces, respectively. Red mesh represents cryo-EM non-protein density. The hydrogen bond between THCV and L490 is shown as a red dotted line. c Time dependence of averaged displacement of the center of THCV molecule modeled in the forward (blue) and backward (pink) orientations relative to the position in the cryo-EM model (the ligands positions were fixed during the first 20 ns). d THCV horizontal pathway is shown as a black curve, with energy minima along the pathway indicated by red segments M1, M2, and M3. Surface of subunit A, subunit B and a groove along the helices S4–S5 contributed by L490 and L568 is colored green, pink and blue, respectively. e Potential of mean force calculated along the horizontal pathway as a function of the distance between the centers of the THCV molecule and the pore axis, with the energy minima M1, M2 and M3 highlighted in cyan. Blue and pink lines indicate hydrogen bonds between THCV and L490 and between THCV and other residues, respectively.