Rosetta in CAPRI rounds 13-19.
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ABSTRACT:
SUBMITTER: Fleishman SJ
PROVIDER: S-EPMC2952713 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We report the performance of the ZDOCK and ZRANK algorithms in CAPRI rounds 13-19 and introduce a novel measure atom contact frequency (ACF). To compute ACF, we identify the residues that most often make contact with the binding partner in the complete set of ZDOCK predictions for each target. We used ACF to predict the interface of the proteins, which, in combination with the biological data available in the literature, is a valuable addition to our docking pipeline. Furthermore, we incorporated a straightforward and efficient clustering algorithm with two purposes: (1) to determine clusters of similar docking poses (corresponding to energy funnels) and (2) to remove redundancies from the final set of predictions. With these new developments, we achieved at least one acceptable prediction for targets 29 and 36, at least one medium-quality prediction for targets 41 and 42, and at least one high-quality prediction for targets 37 and 40; thus, we succeeded for six out of a total of 12 targets.
| S-EPMC3936321 | biostudies-literature
Project description:In CAPRI rounds 13-19, we submitted models that are of acceptable or higher quality for 6 of the total of 13 targets. This success builds on our record in previous CAPRI rounds. The docking problem can be divided into two steps. In the first, translational/rotational and conformational space is searched to generate a pool of docked poses; the success of this search step is measured by whether near-native poses are included in the pool. In the second step, the pool is selected for near-native poses. In our previous assessment of CAPRI results, we suggested that the search problem is largely solved; a remaining problem is to select near-native poses. Our work in these new rounds of CAPRI was guided by this assessment. To solve the selection problem, we used an assortment of criteria on the interfaces of candidate poses. In one extreme, represented by T29, with very little known interface information, our criterion for top models was based on interface prediction. Poses in which the predicted interface residues occurred in interfaces were selected. Our model 1 for T29 was of medium quality. In the other extreme, represented by T40, with reliably known interface information, our selection was solely based on such information. Nine of the ten models submitted for T40 were of high (3 models), medium (4 models), and acceptable (2 models) quality. Our strategy of mixing predicted and known interface information appears to be widely applicable for the selection of near-native poses.
| S-EPMC2948629 | biostudies-literature
Project description:In CAPRI rounds 13-19, the most native-like structure predicted by RosettaDock resulted in two high, one medium, and one acceptable accuracy model out of 13 targets. The current rounds of CAPRI were especially challenging with many unbound and homology modeled starting structures. Novel docking methods, including EnsembleDock and SnugDock, allowed backbone conformational sampling during docking and enabled the creation of more accurate models. For Target 32, ?-amylase/subtilisin inhibitor-subtilisin savinase, we sampled different backbone conformations at an interfacial loop to produce five high-quality models including the most accurate structure submitted in the challenge (2.1 Å ligand rmsd, 0.52 Å interface rmsd). For Target 41, colicin-immunity protein, we used EnsembleDock to sample the ensemble of nuclear magnetic resonance (NMR) models of the immunity protein to generate a medium accuracy structure. Experimental data identifying the catalytic residues at the binding interface for Target 40 (trypsin-inhibitor) were used to filter RosettaDock global rigid body docking decoys to determine high accuracy predictions for the two distinct binding sites in which the inhibitor interacts with trypsin. We discuss our generalized approach to selecting appropriate methods for different types of docking problems. The current toolset provides some robustness to errors in homology models, but significant challenges remain in accommodating larger backbone uncertainties and in sampling adequately for global searches.
| S-EPMC2952725 | biostudies-literature
Project description:Peptide-protein docking is challenging due to the considerable conformational freedom of the peptide. CAPRI rounds 38-45 included two peptide-protein interactions, both characterized by a peptide forming an additional beta strand of a beta sheet in the receptor. Using the Rosetta FlexPepDock peptide docking protocol we generated top-performing, high-accuracy models for targets 134 and 135, involving an interaction between a peptide derived from L-MAG with DLC8. In addition, we were able to generate the only medium-accuracy models for a particularly challenging target, T121. In contrast to the classical peptide-mediated interaction, in which receptor side chains contact both peptide backbone and side chains, beta-sheet complementation involves a major contribution to binding by hydrogen bonds between main chain atoms. To establish how binding affinity and specificity are established in this special class of peptide-protein interactions, we extracted PeptiDBeta, a benchmark of solved structures of different protein domains that are bound by peptides via beta-sheet complementation, and tested our protocol for global peptide-docking PIPER-FlexPepDock on this dataset. We find that the beta-strand part of the peptide is sufficient to generate approximate and even high resolution models of many interactions, but inclusion of adjacent motif residues often provides additional information necessary to achieve high resolution model quality.
| S-EPMC7539656 | biostudies-literature
Project description: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. Second, 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 protein-protein docking server. Despite being fully automated, the last step is computationally too expensive to be included in the server. When 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.
| S-EPMC3027207 | biostudies-literature
Project description:We report the performance of our approaches for protein-protein docking and interface analysis in CAPRI rounds 20-26. At the core of our pipeline was the ZDOCK program for rigid-body protein-protein docking. We then reranked the ZDOCK predictions using the ZRANK or IRAD scoring functions, pruned and analyzed energy landscapes using clustering, and analyzed the docking results using our interface prediction approach RCF. When possible, we used biological information from the literature to apply constraints to the search space during or after the ZDOCK runs. For approximately half of the standard docking challenges we made at least one prediction that was acceptable or better. For the scoring challenges we made acceptable or better predictions for all but one target. This indicates that our scoring functions are generally able to select the correct binding mode.
| S-EPMC3975700 | biostudies-literature
Project description:Critical Assessment of PRediction of Interactions (CAPRI) rounds 37 through 45 introduced larger complexes, new macromolecules, and multistage assemblies. For these rounds, we used and expanded docking methods in Rosetta to model 23 target complexes. We successfully predicted 14 target complexes and recognized and refined near-native models generated by other groups for two further targets. Notably, for targets T110 and T136, we achieved the closest prediction of any CAPRI participant. We created several innovative approaches during these rounds. Since round 39 (target 122), we have used the new RosettaDock 4.0, which has a revamped coarse-grained energy function and the ability to perform conformer selection during docking with hundreds of pregenerated protein backbones. Ten of the complexes had some degree of symmetry in their interactions, so we tested Rosetta SymDock, realized its shortcomings, and developed the next-generation symmetric docking protocol, SymDock2, which includes docking of multiple backbones and induced-fit refinement. Since the last CAPRI assessment, we also developed methods for modeling and designing carbohydrates in Rosetta, and we used them to successfully model oligosaccharide-protein complexes in round 41. Although the results were broadly encouraging, they also highlighted the pressing need to invest in (a) flexible docking algorithms with the ability to model loop and linker motions and in (b) new sampling and scoring methods for oligosaccharide-protein interactions.
| S-EPMC8589291 | biostudies-literature
Project description:A hierarchical approach has been developed for protein-protein docking. In the first step, a Fast Fourier Transform (FFT)-based docking algorithm is used to globally sample all putative binding modes, in which the protein is represented by a reduced model, that is, each side chain on the protein surface is represented by its center of mass. Compared to conventional FFT docking with all-atom models, the FFT docking method with a reduced model is expected to generate more hits because it allows larger side-chain flexibility. Next, the filtered binding modes (normally several thousands) are refined by an iteratively derived knowledge-based scoring function ITScorePP and by considering backbone/loop flexibility using an ensemble docking algorithm. The distance-dependent potentials of ITScorePP were extracted by a physics-based iterative method, which circumvents the long-standing reference state problem in the knowledge-based approaches. With this hierarchical protocol, we have participated in the CAPRI experiments for Rounds 15-19 of 11 targets (T32-T42). In the predictor experiments, we achieved correct binding modes for six targets: three are with high accuracy (T40 for both distinct binding modes, T41, and T42), two are with medium accuracy (T34 and T37), and one is acceptable (T32). In the scorer experiments, of the seven target complexes that contain at least one acceptable mode submitted by the CAPRI predictor groups, we obtained correct binding modes for four targets: three are with high accuracy (T37, T40, and T41) and one is with medium accuracy (T34), suggesting good accuracy and robustness of ITScorePP.
| S-EPMC2952710 | biostudies-literature
Project description:We report the performance of our protein-protein docking pipeline, including the ZDOCK rigid-body docking algorithm, on 19 targets in CAPRI rounds 28-34. Following the docking step, we reranked the ZDOCK predictions using the IRAD scoring function, pruned redundant predictions, performed energy landscape analysis, and utilized our interface prediction approach RCF. In addition, we applied constraints to the search space based on biological information that we culled from the literature, which increased the chance of making a correct prediction. For all but two targets we were able to find and apply biological information and we found the information to be highly accurate, indicating that effective incorporation of biological information is an important component for protein-protein docking. Proteins 2017; 85:408-416. © 2016 Wiley Periodicals, Inc.
| S-EPMC5313317 | biostudies-literature
Project description:We report docking performance on the six targets of Critical Assessment of PRedicted Interactions (CAPRI) rounds 39-45 that involved heteromeric protein-protein interactions and had the solved structures released since the rounds were held. Our general strategy involved protein-protein docking using ZDOCK, reranking using IRAD, and structural refinement using Rosetta. In addition, we made extensive use of experimental data to guide our docking runs. All the experimental information at the amino-acid level proved correct. However, for two targets, we also used protein-complex structures as templates for modeling interfaces. These resulted in incorrect predictions, presumably due to the low sequence identity between the targets and templates. Albeit a small number of targets, the performance described here compared somewhat less favorably with our previous CAPRI reports, which may be due to the CAPRI targets being increasingly challenging.
| S-EPMC7374054 | biostudies-literature