Achieving reliability and high accuracy in automated protein docking: Cluspro, PIPER, SDU, and stability analysis in CAPRI rounds 13–19

Abstract

Our approach to protein-protein docking includes three main steps. First we run PIPER, a rigid body docking program based on the Fast Fourier Transform (FFT) correlation approach, extended to use pairwise interactions potentials. Next, the 1000 best energy conformations are clustered, and the 30 largest clusters are retained for refinement. Third, the stability of the clusters is analyzed by short Monte Carlo simulations, and the structures are refined by the medium-range optimization method SDU. The first two steps of this approach are implemented in the ClusPro 2.0 proteinprotein docking server. Despite being fully automated, the last step is computationally too expensive to be included in the server. Comparing the models obtained in CAPRI rounds 13-19 by ClusPro, by the refinement of the ClusPro predictions, and by all predictor groups, we arrived at three conclusions. First, for the first time in the CAPRI history, our automated ClusPro server was able to compete with the best human predictor groups. Second, selecting the top ranked models, our current protocol reliably generates high quality structures of protein-protein complexes from the structures of separately crystallized proteins, even in the absence of biological information, provided that there is limited backbone conformational change. Third, despite occasional successes, homology modeling requires further improvement to achieve reliable docking results.

In silico and in vitro studies to elucidate the role of Cu2+ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

“…19 To obtain an Ab dimer (lowest free energy), two of the same monomers were used. The ClusPro2.0 server, one of the top performers at CAPRI (Critical Assessment of Predicted Interactions) round [13][14][15][16][17][18][19]20 was used to predict the possible structure of the oligomers. We submitted to ClusPro two monomers to obtain the dimer, which was used to dock with another monomer to form a trimer, and so forth; this process was performed until an Ab pentamer was formed.…”

“…Furthermore, because the Cu 21 and His residues did not interact, the results from this MD simulation contradict those reported in the literature. 9,16,17 Consequently, we evaluated the amino acid residues that interacted with Cu 21 , Asp 23, and Glu 22, as displayed in Figure 4(B-D). The distance between Cu 21 and Asp 23 was lower (2.01 Å ) compared with that between Cu 21 and Glu22 (4.81 Å ) at the end of the simulation [ Fig.…”

“…16,17 Thus, for Ab 1242 in the a-helix conformation, Asp 23 did not interact with Lys 28, The RMSD, Rg, and RMSF values of the interaction between Ab 1-42 and galanthamine were calculated for the entire MD simulation. As displayed in Figure 6(E), the maximum RMSD value for all of the C a atoms was 9 Å .…”

PTEN regulates RPA1 and protects DNA replication forks

“…To provide a structural basis for the physical association of PTEN and the C-terminus of RPA1, in silico docking analysis was used to model the PTEN/RPA complex. Since RPA functions as a trimer of RPA1/RPA2/RPA3, a molecular structure consisting of RPA RPA1(439-616)/RPA2(43-171)/RPA3 [23] was docked with the PTEN crystal structure [24], yielding a single high probability [25] and RPA1 by salmon).…”

“…This docking program filters docked conformations with good surface and charge complementarity and ranks them based on their clustering properties [25]. Then we merged PTEN/RPA and PTEN/OTUB1 model in PyMol to get a RPA/PTEN/OTUB1 complex model.…”