Computational protocol: IFACEwat: the interfacial water-implemented re-ranking algorithm to improve the discrimination of near native structures for protein rigid docking

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Protocol publication

[…] We proposed a new energy-based scoring function to re-rank the results of the initial rigid docking algorithm ZDOCK3.0.2. The scoring function contains a linear combination of potential scores and derived energies that are involved in the protein-protein and protein-water interactions at the complex interfaces (Equation 1). (1) f = w 1 Scor e IFACE + w 2 E LJ_repulsive + w 3 E water - mediated - Hbond + w 4 Δ G interface in which the ScoreIFACE is derived from the combination of shape complementarity, electrostatics, and desolvation (SC+ELEC+DEIFACE using the interface Atomic Contact Energy IFACE) employed in the initial rigid docking algorithm of ZDOCK3.0.2. The ELJ_repulsive and Ewater-mediated-Hbond are Lennard-Jones repulsive and water-mediated Hydrogen bond energies respectively to represent the protein-water interactions. Finally the ΔGinterface is the free energy change of the interface representing the interactions between the protein partners. The four parameters w1, w2, w3, and w4 are separate weights of the corresponding potentials. Flowchart of the whole process is shown in Figure . [...] The water effect and contacts are represented by the energies of the protein-water dispersion (ELJ_repulsive) and the water-mediated Hydrogen bonds at the interfaces (Ewater-mediated-Hbond). Initially, we extracted the complex interfaces and subsequently followed a process of adding water molecules. There was no water molecule found in the interfaces of the predicted complexes by ZDOCK3.0.2 because no water was so far involved in the previous dockings of the protein complexes.We extracted the complex interfaces using INTERVOR [], a Voronoi-based algorithm modeling and computing macromolecular interfaces. Repeated interface extractions for all the crystalized complexes in the dataset were firstly performed and then mapped back to the original structures to confirm the reliability of the INTERVOR package. Our preliminary results showed that 159/159 interfaces of the protein complexes were successfully extracted and superimposed with the original crystalized structures. Only after being cross-confirmed of its fidelity, INTERVOR was used to extract the complex interfaces of all the 2000 predictions in the same protocol for each protein complex in the dataset.Then, we applied DOWSER to explicitly add water molecules into the protein complex interfaces. DOWSER is a modeling package that investigates free energy of hydrophilic cavities and surfaces of proteins and adds water molecules into the cavities in which water exists []. Similarly, we tested the reliability and accuracy of the DOWSER application in recovering internal water of the protein interfaces by performing a simulation of adding water into interfacial cavities of protein complexes for the dataset of the 159 crystal structures. It was demonstrated that 91.3% of internal water molecules were successfully recovered (where the predicted water positions were within a distance ≤ 1.5Å from the water positions in the crystal structures). Therefore, it suggests that DOWSER could be a reliable tool to recover the water in the protein crystalized structures and thus it was used to predict the water positions for the interfaces of protein complexes in our work.After adding water into each of the extracted interfaces of the protein complexes, we conducted the structural minimization using AMBER10 (force field ff99SB) to stabilize the water positions with respect to the whole structure of the protein interface. Initially, 2500 steps of steepest descent were performed and followed by another 500 steps of conjugate gradient minimization. During the minimization, no restraint was applied and random initial velocities were used to maintain the robustness. The minimized water-containing structures of the protein interfaces were then subject to the next process of energy calculations. […]

Pipeline specifications

Software tools ZDOCK, AMBER
Databases SCOR
Application Protein interaction analysis