Blind prediction of interfacial water positions in CAPRI

Abstract

We report the first assessment of blind predictions of water positions at protein-protein interfaces, performed as part of the CAPRI (Critical Assessment of Predicted Interactions) community-wide experiment. Groups submitting docking predictions for the complex of the DNase domain of colicin E2 and Im2 immunity protein (CAPRI target 47), were invited to predict the positions of interfacial water molecules using the method of their choice. The predictions – 20 groups submitted a total of 195 models – were assessed by measuring the recall fraction of water-mediated protein contacts. Of the 176 high or medium quality docking models – a very good docking performance per se – only 44% had a recall fraction above 0.3, and a mere 6% above 0.5. The actual water positions were in general predicted to an accuracy level no better than 1.5 Å, and even in good models about half of the contacts represented false positives. This notwithstanding, three hotspot interface water positions were quite well predicted, and so was one of the water positions that is believed to stabilize the loop that confers specificity in these complexes. Overall the best interface water predictions was achieved by groups that also produced high quality docking models, indicating that accurate modelling of the protein portion is a determinant factor. The use of established molecular mechanics force fields, coupled to sampling and optimization procedures also seemed to confer an advantage. Insights gained from this analysis should help improve the prediction of protein-water interactions and their role in stabilizing protein complexes.

On the ability of molecular dynamics simulation and continuum electrostatics to treat interfacial water molecules in protein-protein complexes

“…3c), the values are slightly lower, with a distribution centering on f w (nat) = 0.5, balancing between the “good” and “excellent” categories. Such values lie a tenth of a point lower than what was found previously19, but it should be noted that those simulations held the relative position of the monomers fixed, whereas in our work everything was free to move. One can also assume that our simulation temperature of 300 K will have an adverse effect on f w (nat) values, as the crystal structure was solved at cryogenic temperatures (100 K).…”

“…2; this definition is the same as in ref. 19, where it has also been shown that these two measures correlate. As Fig.…”

“…It was clear from the experiment that further work in the prediction of interfacial water molecules was required. Nevertheless, the results were encouraging: several of the conserved water molecules, which define the interface hot spot, were correctly predicted, as was at least one of the water molecules responsible for the specificity for the family of complexes19. The more sophisticated methods employed, which often combine the use of classical empirical force fields with additional sampling and energy minimization, were found to be more successful than simpler water placement methodologies.…”

“…The complex between the DNase domain of colicin E2 and its cognate Im2 immunity protein18, resolved at 1.72 Å resolution at a temperature of 100K, featured as Target 47 in the CAPRI protein docking experiment19. With high-quality template structures of the complex available in the PDB, both cognate and non-cognate, the focus of the experiment lay in the prediction of the water positions at the protein-protein interface.…”

“…As our study systems we have chosen three distinct but challenging systems to test the methodologies, which are the two complexes already discussed before: (i) the barnase/barstar complex15 (hereafter abbreviated by Barnase) and (ii) colicin DNase E2/Im2 protein complex18 or CAPRI T4719, and furthermore, (iii) the antifreeze protein Maxi3536. All systems are shown in Fig.…”