Figure 7.

Free Energy Profile Required for the Passage of Uridine Triphosphate (UTP) and Activated Sofosbuvir (SOF) Through the NTP Tunnel of NS5B Polymerase of Genotype 1b HCV. (a) NS5B polymerase manifesting the A207, A218, C316 and Q464 wild-types as constructed based on the nucleotide sequence of HCV strains obtained from baseline sera from a patient who achieved an SVR after ledipasvir (LDV)/SOF therapy. (b) Single mutation of C316N was added to the polymerase shown in Fig. 3a. (c) Single mutation of A218S was added to the polymerase shown in Fig. 3a. (d) Double mutations of A218S and C316N were added to the polymerase shown in Fig. 3a. (e) Quadruple mutations of A207T, A218S, C316N and Q464E mutations were added to the polymerase shown in Fig. 3a. (f) A218S mutation was reverted to A218 wild-type in the polymerase shown in Fig. 3e. (g) NS5B polymerase manifesting A207T, A218S, C316N and Q464E mutations constructed based on nucleotide sequences of HCV strains obtained at the time of virologic failure in patients receiving LDV/SOF therapy. (h) A218S mutation was reverted to A218 wild-type in the polymerase shown in Fig. 3f. Molecular dynamics simulations were performed 3 times for each situation, and the mean, maximal, and minimal values are show in figure.