Figure 8. Direct and indirect coevolution links in NS5B.

The intra-NS5B coevolving residues, issued from BIS² analysis, correspond to the direct physical interaction 239–293 (green; data from cluster 8 of genotype 4, see Supplementary Figure 3), and indirect coevolution links for the three residues colored cyan (47, 77, 517; data from cluster 4 of genotype 2b, see Supplementary Figure 2). Coevolution links between NS5B and NS3 protease, NS3 helicase, E2 and NS5A involve four residues (magenta) located on NS5B surface (data from cluster 12 of genotype 4, see Supplementary Figure 3). Three of these residues (120, 124, 128) belong to the same side of an α-helix and the neighbouring fourth one (258) is located on the surface of another α-helix oriented on the same direction. These four residues, coevolving with residues in NS3, NS5A and E2 (also coloured magenta), support the hypothesis of existing interactions of NS5B with these proteins. Note that the four protein structures are not represented at the same scale.