Abstract
In view of the increasing interest both in inhibitors of protein-protein interactions and in protein drugs themselves, analysis of the three-dimensional structure of protein-protein complexes is assuming greater relevance in drug design. In the many cases where an experimental structure is not available, protein-protein docking becomes the method of choice for predicting the arrangement of the complex. However, reliably scoring protein-protein docking poses is still an unsolved problem. As a consequence, the screening of many docking models is usually required in the analysis step, to possibly single out the correct ones. Here, making use of exemplary cases, we review our recently introduced methods for the analysis of protein complex structures and for the scoring of protein docking poses, based on the use of inter-residue contacts and their visualization in inter-molecular contact maps. We also show that the ensemble of tools we developed can be used in the context of rational drug design targeting protein-protein interactions.
Highlights
Protein-protein interactions are receiving considerable attention as targets for rational drug design.Interest in both inhibitors of protein-protein interactions [1,2,3,4,5,6] and protein drugs themselves [7,8,9,10] is constantly increasing
When measuring the conservation of the various contacts in several ensembles of docking models submitted to CAPRI (Critical Assessment of PRedicted Interactions), a community-wide blind docking experiment, we interestingly found that most conserved contacts in each ensemble usually correspond to the “native” ones, i.e., those observed in the experimental structure [20]
Based on this promising observation, we developed CONSRANK (CONSensus-RANKing), a consensus approach to the scoring and ranking of docking models, which ranks models based on their ability to match the most conserved contacts in the ensemble to which they belong [21]
Summary
Protein-protein interactions are receiving considerable attention as targets for rational drug design. From the COCOMAPS tables, we see that the BC interface area is 1022 Å2 (vs 776 Å2 of the AC interface) and that buried residues (more than 90%) are all hydrophobic: besides Leu at P1, Ile and Phe115 As mentioned above, this double interface trypsin-inhibitor complex was a target in the CAPRI experiment (Round 18). The third model, ranked 300th, is instead incorrect and mostly matches contacts with a very low conservation rate It matches the well-conserved contact between trypsin Thr144 and API-A Lys, which is a native one, being present in the corresponding crystal structure at the Leu interface. Ab2-E5.2 (PDB ID: 1DVF [41]), despite the obvious differences in sequence This was immediately clear from comparison of the respective contact maps (see Figure 3) and was confirmed by detailed analysis of the 3D structures
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