Mutation interaction types. Four mutation interaction types are present. Labelled spheres indicate which amino acid at specified position is present related to PDB-Id. A: Simple evolutionary replacements (red) around the blue and green interacting residue spheres. B: Interacting AL9 motifs (blue and green) with evolutionary residue substitution without loss of interaction. Mutations at one or at both interaction partner are possible. B1: Asp 115 at the second position of AL9-motif pattern representative AD 115GIMIGTL interacts with Ala 91 or Pro 91 of AL9-motif pattern representative A[SD] 85WLFTT[AP] 91LL. This is made possible by the same orientation of Ala 91 and Pro 91 towards its interacting counterpart. B2: Analogously, fourth position of AL9-motif pattern representative AFT[MA] 56YLSMLL is designed variable with Ala 56 or Met 56 and interacts with Asp 85 or Ser 85 reason by same orientation in space. C: If contact information will be lost by mutation, the responsible destabilizing amino acid will be compensated by another position, in order to maintain attractive residue pair interaction . C1/C2: Ile 148 and Val 148 at fifth position of AL9-motif pattern representative AMLY[VIA] 148LYVL (blue) are able to interact with Ala 114 at sixth position of LI8-motif representative LAL 111
114DGI (green). C3: Mutation with Ala 148 causes that contact will be lost reason by to short distance to Ala 114 counterpart. Here, Leu 111 at third position of LI8-motif compensates the destabilizing amino acid. Evolution aims at maintaining stabilizing interactions. D: Trp 137/142 is an evolutionary coupling residue which interacts with Ile 129 or Val 124 by full changeable residue environment around Trp 137/142. This means that the evolutionary degree of freedom allows it to change all variable positions of an interacting pattern by keeping the conserved interaction residue.