Modeling of protein complexes in CASP14 with emphasis on the interaction interface prediction.
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ABSTRACT:
SUBMITTER: Dapkunas J
PROVIDER: S-EPMC9292421 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Proteins involved in interactions throughout the course of evolution tend to co-evolve and compensatory changes may occur in interacting proteins to maintain or refine such interactions. However, certain residue pair alterations may prove to be detrimental for functional interactions. Hence, determining co-evolutionary pairings that could be structurally or functionally relevant for maintaining the conservation of an inter-protein interaction is important. Inter-protein co-evolution analysis in several complexes utilizing multiple existing methodologies suggested that co-evolutionary pairings can occur in spatially proximal and distant regions in inter-protein interactions. Subsequently, the Co-Var (Correlated Variation) method based on mutual information and Bhattacharyya coefficient was developed, validated, and found to perform relatively better than CAPS and EV-complex. Interestingly, while applying the Co-Var measure and EV-complex program on a set of protein-protein interaction complexes, co-evolutionary pairings were obtained in interface and non-interface regions in protein complexes. The Co-Var approach involves determining high degree co-evolutionary pairings that include multiple co-evolutionary connections between particular co-evolved residue positions in one protein with multiple residue positions in the binding partner. Detailed analyses of high degree co-evolutionary pairings in protein-protein complexes involved in cancer metastasis suggested that most of the residue positions forming such co-evolutionary connections mainly occurred within functional domains of constituent proteins and substitution mutations were also common among these positions. The physiological relevance of these predictions suggested that Co-Var can predict residues that could be crucial for preserving functional protein-protein interactions. Finally, Co-Var web server (http://www.hpppi.iicb.res.in/ishi/covar/index.html) that implements this methodology identifies co-evolutionary pairings in intra and inter-protein interactions.
| S-EPMC8271121 | biostudies-literature
Project description:Accurate prediction of residue-residue distances is important for protein structure prediction. We developed several protein distance predictors based on a deep learning distance prediction method and blindly tested them in the 14th Critical Assessment of Protein Structure Prediction (CASP14). The prediction method uses deep residual neural networks with the channel-wise attention mechanism to classify the distance between every two residues into multiple distance intervals. The input features for the deep learning method include co-evolutionary features as well as other sequence-based features derived from multiple sequence alignments (MSAs). Three alignment methods are used with multiple protein sequence/profile databases to generate MSAs for input feature generation. Based on different configurations and training strategies of the deep learning method, five MULTICOM distance predictors were created to participate in the CASP14 experiment. Benchmarked on 37 hard CASP14 domains, the best performing MULTICOM predictor is ranked 5th out of 30 automated CASP14 distance prediction servers in terms of precision of top L/5 long-range contact predictions (i.e. classifying distances between two residues into two categories: in contact (< 8 Angstrom) and not in contact otherwise) and performs better than the best CASP13 distance prediction method. The best performing MULTICOM predictor is also ranked 6th among automated server predictors in classifying inter-residue distances into 10 distance intervals defined by CASP14 according to the precision of distance classification. The results show that the quality and depth of MSAs depend on alignment methods and sequence databases and have a significant impact on the accuracy of distance prediction. Using larger training datasets and multiple complementary features improves prediction accuracy. However, the number of effective sequences in MSAs is only a weak indicator of the quality of MSAs and the accuracy of predicted distance maps. In contrast, there is a strong correlation between the accuracy of contact/distance predictions and the average probability of the predicted contacts, which can therefore be more effectively used to estimate the confidence of distance predictions and select predicted distance maps. The software package, source code, and data of DeepDist2 are freely available at https://github.com/multicom-toolbox/deepdist and https://zenodo.org/record/4712084#.YIIM13VKhQM.
| S-EPMC8504632 | biostudies-literature
Project description:For CASP14, we developed deep learning-based methods for predicting homo-oligomeric and hetero-oligomeric contacts and used them for oligomer modeling. To build structure models, we developed an oligomer structure generation method that utilizes predicted interchain contacts to guide iterative restrained minimization from random backbone structures. We supplemented this gradient-based fold-and-dock method with template-based and ab initio docking approaches using deep learning-based subunit predictions on 29 assembly targets. These methods produced oligomer models with summed Z-scores 5.5 units higher than the next best group, with the fold-and-dock method having the best relative performance. Over the eight targets for which this method was used, the best of the five submitted models had average oligomer TM-score of 0.71 (average oligomer TM-score of the next best group: 0.64), and explicit modeling of inter-subunit interactions improved modeling of six out of 40 individual domains (ΔGDT-TS > 2.0).
| S-EPMC8616806 | biostudies-literature
Project description:Protein-protein interactions drive wide-ranging molecular processes, and characterizing at the atomic level how proteins interact (beyond just the fact that they interact) can provide key insights into understanding and controlling this machinery. Unfortunately, experimental determination of three-dimensional protein complex structures remains difficult and does not scale to the increasingly large sets of proteins whose interactions are of interest. Computational methods are thus required to meet the demands of large-scale, high-throughput prediction of how proteins interact, but unfortunately both physical modeling and machine learning methods suffer from poor precision and/or recall. In order to improve performance in predicting protein interaction interfaces, we leverage the best properties of both data- and physics-driven methods to develop a unified Geometric Deep Neural Network, "PInet" (Protein Interface Network). PInet consumes pairs of point clouds encoding the structures of two partner proteins, in order to predict their structural regions mediating interaction. To make such predictions, PInet learns and utilizes models capturing both geometrical and physicochemical molecular surface complementarity. In application to a set of benchmarks, PInet simultaneously predicts the interface regions on both interacting proteins, achieving performance equivalent to or even much better than the state-of-the-art predictor for each dataset. Furthermore, since PInet is based on joint segmentation of a representation of a protein surfaces, its predictions are meaningful in terms of the underlying physical complementarity driving molecular recognition. PInet scripts and models are available at https://github.com/FTD007/PInet. Supplementary data are available at Bioinformatics online.
| S-EPMC8428585 | biostudies-literature
Project description:Substantial progresses in protein structure prediction have been made by utilizing deep-learning and residue-residue distance prediction since CASP13. Inspired by the advances, we improve our CASP14 MULTICOM protein structure prediction system by incorporating three new components: (a) a new deep learning-based protein inter-residue distance predictor to improve template-free (ab initio) tertiary structure prediction, (b) an enhanced template-based tertiary structure prediction method, and (c) distance-based model quality assessment methods empowered by deep learning. In the 2020 CASP14 experiment, MULTICOM predictor was ranked seventh out of 146 predictors in tertiary structure prediction and ranked third out of 136 predictors in inter-domain structure prediction. The results demonstrate that the template-free modeling based on deep learning and residue-residue distance prediction can predict the correct topology for almost all template-based modeling targets and a majority of hard targets (template-free targets or targets whose templates cannot be recognized), which is a significant improvement over the CASP13 MULTICOM predictor. Moreover, the template-free modeling performs better than the template-based modeling on not only hard targets but also the targets that have homologous templates. The performance of the template-free modeling largely depends on the accuracy of distance prediction closely related to the quality of multiple sequence alignments. The structural model quality assessment works well on targets for which enough good models can be predicted, but it may perform poorly when only a few good models are predicted for a hard target and the distribution of model quality scores is highly skewed. MULTICOM is available at https://github.com/jianlin-cheng/MULTICOM_Human_CASP14/tree/CASP14_DeepRank3 and https://github.com/multicom-toolbox/multicom/tree/multicom_v2.0.
| S-EPMC8671168 | biostudies-literature
Project description:We present the results for CAPRI Round 50, the fourth joint CASP-CAPRI protein assembly prediction challenge. The Round comprised a total of twelve targets, including six dimers, three trimers, and three higher-order oligomers. Four of these were easy targets, for which good structural templates were available either for the full assembly, or for the main interfaces (of the higher-order oligomers). Eight were difficult targets for which only distantly related templates were found for the individual subunits. Twenty-five CAPRI groups including eight automatic servers submitted ~1250 models per target. Twenty groups including six servers participated in the CAPRI scoring challenge submitted ~190 models per target. The accuracy of the predicted models was evaluated using the classical CAPRI criteria. The prediction performance was measured by a weighted scoring scheme that takes into account the number of models of acceptable quality or higher submitted by each group as part of their five top-ranking models. Compared to the previous CASP-CAPRI challenge, top performing groups submitted such models for a larger fraction (70-75%) of the targets in this Round, but fewer of these models were of high accuracy. Scorer groups achieved stronger performance with more groups submitting correct models for 70-80% of the targets or achieving high accuracy predictions. Servers performed less well in general, except for the MDOCKPP and LZERD servers, who performed on par with human groups. In addition to these results, major advances in methodology are discussed, providing an informative overview of where the prediction of protein assemblies currently stands.
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Project description:Structural insight of the protein-protein interaction (PPI) interface can provide knowledge about the kinetics, thermodynamics and molecular functions of the complex while elucidating its role in diseases and further enabling it as a potential therapeutic target. However, owing to experimental lag in solving protein-protein complex structures, three-dimensional (3D) knowledge of the PPI interfaces can be gained via computational approaches like molecular docking and post-docking analyses. Despite development of numerous docking tools and techniques, success in identification of native like interfaces based on docking score functions is limited. Hence, we employed an in-depth investigation of the structural features of the interface that might successfully delineate native complexes from non-native ones. We identify interface properties, which show statistically significant difference between native and non-native interfaces belonging to homo and hetero, protein-protein complexes. Utilizing these properties, a support vector machine (SVM) based classification scheme has been implemented to differentiate native and non-native like complexes generated using docking decoys. Benchmarking and comparative analyses suggest very good performance of our SVM classifiers. Further, protein interactions, which are proven via experimental findings but not resolved structurally, were subjected to this approach where 3D-models of the complexes were generated and most likely interfaces were predicted. A web server called Protein Complex Prediction by Interface Properties (PCPIP) is developed to predict whether interface of a given protein-protein dimer complex resembles known protein interfaces. The server is freely available at http://www.hpppi.iicb.res.in/pcpip/ .
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Project description:Protein-DNA interactions are the physical basis of gene expression and DNA modification. Structural models that reveal these interactions are essential for their understanding. As only a limited number of structures for protein-DNA complexes have been determined by experimental methods, computation methods provide a potential way to fill the need. We have developed the DISPLAR method to predict DNA binding sites on proteins. Predicted binding sites have been used to assist the building of structural models by docking, either by guiding the docking or by selecting near-native candidates from the docked poses. Here we applied the DISPLAR method to predict the DNA binding sites for 20 DNA-binding proteins, which have had their DNA binding sites characterized by NMR chemical shift perturbation. For two of these proteins, the structures of their complexes with DNA have also been determined. With the help of the DISPLAR predictions, we built structural models for these two complexes. Evaluations of both the DNA binding sites for 20 proteins and the structural models of the two protein-DNA complexes against experimental results demonstrate the significant promise of our model-building approach.
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Project description:A method for predicting protein-protein interactions based on detected protein complexes is proposed to repair deficient interactions derived from high-throughput biological experiments. Protein complexes are pruned and decomposed into small parts based on the adaptive k-cores method to predict protein-protein interactions associated with the complexes. The proposed method is adaptive to protein complexes with different structure, number, and size of nodes in a protein-protein interaction network. Based on different complex sets detected by various algorithms, we can obtain different prediction sets of protein-protein interactions. The reliability of the predicted interaction sets is proved by using estimations with statistical tests and direct confirmation of the biological data. In comparison with the approaches which predict the interactions based on the cliques, the overlap of the predictions is small. Similarly, the overlaps among the predicted sets of interactions derived from various complex sets are also small. Thus, every predicted set of interactions may complement and improve the quality of the original network data. Meanwhile, the predictions from the proposed method replenish protein-protein interactions associated with protein complexes using only the network topology.
| S-EPMC4333188 | biostudies-literature
Project description:The degree of proteins structural organization ranges from highly structured, compact folding to intrinsic disorder, where each degree of self-organization corresponds to specific functions: well-organized structural motifs in enzymes offer a proper environment for precisely positioned functional groups to participate in catalytic reactions; at the other end of the self-organization spectrum, intrinsically disordered proteins act as binding hubs via the formation of multiple, transient and often non-specific interactions. This review focusses on cases where structurally organized proteins or domains associate with highly disordered protein chains, leading to the formation of interfaces with varying degrees of fuzziness. We present a review of the computational methods developed to provide us with information on such fuzzy interfaces, and how they integrate experimental information. The discussion focusses on two specific cases, microtubules and homologous recombination nucleoprotein filaments, where a network of intrinsically disordered tails exerts regulatory function in recruiting partner macromolecules, proteins or DNA and tuning the atomic level association. Notably, we show how computational approaches such as molecular dynamics simulations can bring new knowledge to help bridging the gap between experimental analysis, that mostly concerns ensemble properties, and the behavior of individual disordered protein chains that contribute to regulation functions.
| S-EPMC8533853 | biostudies-literature