Fig. 3

a Wild type protease (in yellow and blue) with an inhibitor (NFV, in green) (PDB code: 3EKX). We highlight the ten most important positions according to RF: 10, 90, 54, 46, 71, 88, 84, 30, 20 and 82. These positions are scattered throughout the protein and only a few belong to the drug binding site (e.g. 30, 82 and 84). Mutations at the binding site reduce the affinity for the inhibitor, but can impair the protease catalytic activity as a collateral damage. Mutations in distant residues are typically concurrent with these binding site mutations and often have a compensatory role (e.g. stabilizing the protease structure or restoring the catalytic activity). Position 30 appears to be important only in the case of the NFV drug, while the other positions are found in all (or almost all) protease inhibitors. This agrees with the literature [2]. b Binding pocket of the reverse transcriptase (in yellow) with an NNRTI (NVP, in pink) (PDB code: 3V81). We highlight the five most important positions for NVP according to RF: 103, 181, 190, 188 and 101. All these positions reside in the NNRTI binding pocket of the enzyme, and also appear in the other NNRTIs analyzed. Thus, in EFV, we find 100 (but not 181) in the top 5; and in ETR, we have 179 instead of 188 (also highlighted). Positions 103 and 101 are located near the entry of the inhibitor binding pocket and, when mutated, interfere with the entrance of the inhibitor to the binding site. Y181 and Y188 have a crucial contribution the NVP binding via stacking interactions between its side chains and the inhibitor aromatic groups. G190 mutations lead to resistance through steric hindrance, because of the substitution by a more voluminous side chain. L100 effect is also related to steric hindrance [2]