Molecular modeling study on the drug resistance mechanism of NS5B polymerase to TMC647055

Huiqun Wang,1Wei Cui,1Chenchen Guo,1Bo-Zhen Chen*1 and Mingjuan Ji1

*Corresponding author:Bo-Zhen Chen

E-mail address: . Tel.: +86 10 88256129; fax: +86 10 88256092

1School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Yuquan Road 19A, 100049, Beijing, P. R. China.

Table S1. Binding free energiesand individual energy terms of NS5B/TMC647055 (NS5B/TMC) calculated

byMM/PBSAmethod(kcal/mol)

NS5B/TMC / ΔEelea / ΔEvdwb / ΔGPBc / ΔGSAd / ΔHbinde
L392V / -10.88+1.58 / -46.26+2.89 / 12.22+1.25 / -6.13+0.24 / -51.04+2.85
P495V / -10.77+1.75 / -46.56+3.34 / 12.94+1.33 / -6.22+0.28 / -50.60+3.45
P495I / -6.33+2.11 / -46.15+2.76 / 9.29+1.65 / -6.25+0.24 / -49.45+2.62

Fig. S1. Distances between atom CG (H33WT) and atom C17 (TMC), between atom CE1 (H33WT) and atom C17 (TMC), between atom CG (H33WT) and atom CH2 (W397 WT),between atom CE1 (H33WT) and atom CH2 (W397 WT),between atom CE3 (W397WT) and atom C24 (TMC), between atom CE2 (W397WT) and atom C24 (TMC) in NS5BWT/TMC complex as well as the corresponding distance in NS5BL392I/TMC complex during 29 ns MD simulation are displayed in (a), (b), (c), (d), (e), and (f), respectively.The d represents the distancesin the NS5BWT/TMC and NS5BL392I/TMC complexes.

Fig.S2. The root-mean-square-deviations (rmsds) of the backbone atoms (CA, N, C) (a) and TMC647055 (b) in the NS5BL392V/TMC, NS5BP495V/TMC, and NS5BP495I/TMC complex relative to the starting structures.

Fig. S3. The binding free energy (a) and electrostatic interaction (b) spectrums of the NS5BL392V/TMC, NS5BP495V/TMC, and NS5BP495I/TMC complexes according to the MM/GBSA decomposition analysis. The X-axis represents the key residue numbers of the NS5B polymerase.

Fig. S4.Distances between atom CG (H33WT) and atom C17 (TMC), between atom CE1 (H33WT) and atom C17 (TMC), between atom CG (H33WT) and atom CH2 (W397 WT),between atom CE1 (H33WT) and atom CH2 (W397 WT),between atom CE3 (W397WT) and atom C24 (TMC)in NS5BWT/TMC complex as well as the corresponding distance in NS5BP495T/TMC complex during 29 ns MD simulation are displayed in (a), (b), (c), (d),and (e), respectively.The d represents the distancesin the NS5BWT/TMC and NS5BP495T/TMC complexes.

Fig. S5. Distances between atom CG (H33WT) and atom C17 (TMC), between atom CE1 (H33WT) and atom C17 (TMC), between atom CG (H33WT) and atom CH2 (W397WT),between atom CE1 (H33WT) and atom CH2 (W397WT),between atom CE3 (W397WT) and atom C24 (TMC) in NS5BWT/TMC complex as well as the corresponding distance in NS5BP495S/TMC complex during 29 ns MD simulation are displayed in (a), (b), (c), (d),and (e), respectively.The d represents the distancesin the NS5BWT/TMC and NS5BP495S/TMC complexes.

Fig. S6. Distances between atom CG (H33WT) and atom C17 (TMC), between atom CE1 (H33WT) and atom C17 (TMC), between atom CG (H33WT) and atom CH2 (W397 WT),between atom CE1 (H33WT) and atom CH2 (W397WT),between atom CE3 (W397WT) and atom C24 (TMC) in NS5BWT/TMCcomplex as well as the corresponding distance in NS5BP495L/TMC complex during 29 ns MD simulation are displayed in (a), (b), (c), (d),and (e), respectively. The d represents the distancesin the NS5BWT/TMC and NS5BP495L/TMC complexes.