Hypothetical models of bevirimat binding to the CA-SP1 junction. Fitting of bevirimat into model A and B according to crosslinking and mutation data. Since the C-30 analog crosslinked within only four residues (VLAE) spanning the CA-SP1 cleavage site and the C-28 analog crosslinked within an area four residues upstream from the CA-SP1 cleavage site, we could orient the drug such that the C28 carboxylic acid group is toward the N-terminus and the C3 dimethylsuccinyl group is toward the C-terminus of the helix. Top panel: Top view of models A&B. In model A, hydrophobic and hydrophilic faces of one helix are making respective contacts with neighboring helices. In model B, the hydrophobic faces of all six helices are pointing toward the center of the bundle. Bevirimat is shown as gray ball-and-stick atoms. Interacting amino acids are also shown in ball-and-stick mode; hydrophobic residues are highlighted in red and hydrophilic residues are highlighted in blue. Models were constructed using six identical NMR structures of a peptide spanning the CA-SP1 region (PDB 1U57). Only sequence spanning the putative helix was used (GHKARVLAEAMSQVTNSATIMMQR). For simplicity, only sequence HKARVLAEAMSQVTNSAT is shown after the energy minimization process. Residue H358 is labeled in magenta. The most common in vitro resistant mutation, A364, is labeled in yellow. The most common resistant polymorphism, V370, is labeled in red. Bottom panel: Side view of models A&B.