Structural Interface Parameters Are Discriminatory in Recognising Near-Native Poses of Protein-Protein Interactions

Abstract

Interactions at the molecular level in the cellular environment play a very crucial role in maintaining the physiological functioning of the cell. These molecular interactions exist at varied levels viz. protein-protein interactions, protein-nucleic acid interactions or protein-small molecules interactions. Presently in the field, these interactions and their mechanisms mark intensively studied areas. Molecular interactions can also be studied computationally using the approach named as Molecular Docking. Molecular docking employs search algorithms to predict the possible conformations for interacting partners and then calculates interaction energies. However, docking proposes number of solutions as different docked poses and hence offers a serious challenge to identify the native (or near native) structures from the pool of these docked poses. Here, we propose a rigorous scoring scheme called DockScore which can be used to rank the docked poses and identify the best docked pose out of many as proposed by docking algorithm employed. The scoring identifies the optimal interactions between the two protein partners utilising various features of the putative interface like area, short contacts, conservation, spatial clustering and the presence of positively charged and hydrophobic residues. DockScore was first trained on a set of 30 protein-protein complexes to determine the weights for different parameters. Subsequently, we tested the scoring scheme on 30 different protein-protein complexes and native or near-native structure were assigned the top rank from a pool of docked poses in 26 of the tested cases. We tested the ability of DockScore to discriminate likely dimer interactions that differ substantially within a homologous family and also demonstrate that DOCKSCORE can distinguish correct pose for all 10 recent CAPRI targets.

Stepwise visualization of membrane pore formation by suilysin, a bacterial cholesterol-dependent cytolysin

“…( C and D ) Interacting residues between a given dimer of domain 1 (shown in orange) mapped onto the crystal structure in the prepore ( C ) and pore ( D ) respectively. We consider two residues as interacting (interface residue) if their corresponding Cβ atoms were found within the distance of 7 Å ( Malhotra et al, 2014 ). 32 common interacting residues (shown in magenta) for domain 1 were identified by comparing the interacting residues of the corresponding prepore and pore dimers, suggesting that approximately 50% of the interface is preserved between the prepore and pore fit.…”

“…We further analysed the contacts in adjacent monomers of domain 1 in the prepore and pore fit ( Figure 1—figure supplement 3C,D ). We considered two residues as interacting (interface residue) if their corresponding Cβ atoms are within a distance of 7 Å ( Malhotra et al, 2014 ).…”

Anin silicoapproach towards the identification of novel inhibitors of the TLR-4 signaling pathway

“…The residues of the BB loop and αC helix of TRAM and the functionally important Leu 6 residue of VIPER were used to guide the docking. The complexes belonging to clusters having low energy poses, produced by both the programs were ranked using another in-house program, DockScore (Malhotra et al, 2014) to recognise near-native interactions and best poses. The top-ten ranked models were chosen for further detailed analysis of the various interactions possible at the binding interface.…”

“…(Malhotra et al, 2014), identified the model belonging to HADDOCKgenerated cluster 8 as the top scoring one. In this model of the complex, the TRAM binds at the interface of the dimer.…”

DOCKSCORE: a webserver for ranking protein-protein docked poses

“…There are several scoring programs available as a downloadable package [ 19 - 21 ] in order to re-rank the docked poses, but the webserver implementation or availability for easy access is less common [ 17 , 22 , 23 ]. In this article, we report the availability of DockScore in the public domain as a webserver for the scientific community.…”