Deep learning techniques have significantly advanced the field of protein structure prediction. LOMETS3 (https://zhanglab.ccmb.med.umich.edu/LOMETS/) is a new generation meta-server approach to template-based protein structure prediction and function annotation, which integrates newly developed deep learning threading methods. For the first time, we have extended LOMETS3 to handle multi-domain proteins and to construct full-length models with gradient-based optimizations. Starting from a FASTA-formatted sequence, LOMETS3 performs four steps of domain boundary prediction, domain-level template identification, full-length template/model assembly and structure-based function prediction. The output of LOMETS3 contains (i) top-ranked templates from LOMETS3 and its component threading programs, (ii) up to 5 full-length structure models constructed by L-BFGS (limited-memory Broyden–Fletcher–Goldfarb–Shanno algorithm) optimization, (iii) the 10 closest Protein Data Bank (PDB) structures to the target, (iv) structure-based functional predictions, (v) domain partition and assembly results, and (vi) the domain-level threading results, including items (i)–(iii) for each identified domain. LOMETS3 was tested in large-scale benchmarks and the blind CASP14 (14th Critical Assessment of Structure Prediction) experiment, where the overall template recognition and function prediction accuracy is significantly beyond its predecessors and other state-of-the-art threading approaches, especially for hard targets without homologous templates in the PDB. Based on the improved developments, LOMETS3 should help significantly advance the capabilitymore »
Most proteins in nature contain multiple folding units (or domains). The revolutionary success of AlphaFold2 in single-domain structure prediction showed potential to extend deep-learning techniques for multi-domain structure modeling. This work presents a significantly improved method, DEMO2, which integrates analogous template structural alignments with deep-learning techniques for high-accuracy domain structure assembly. Starting from individual domain models, inter-domain spatial restraints are first predicted with deep residual convolutional networks, where full-length structure models are assembled using L-BFGS simulations under the guidance of a hybrid energy function combining deep-learning restraints and analogous multi-domain template alignments searched from the PDB. The output of DEMO2 contains deep-learning inter-domain restraints, top-ranked multi-domain structure templates, and up to five full-length structure models. DEMO2 was tested on a large-scale benchmark and the blind CASP14 experiment, where DEMO2 was shown to significantly outperform its predecessor and the state-of-the-art protein structure prediction methods. By integrating with new deep-learning techniques, DEMO2 should help fill the rapidly increasing gap between the improved ability of tertiary structure determination and the high demand for the high-quality multi-domain protein structures. The DEMO2 server is available at https://zhanggroup.org/DEMO/.
- Publication Date:
- NSF-PAR ID:
- 10368739
- Journal Name:
- Nucleic Acids Research
- Volume:
- 50
- Issue:
- W1
- Page Range or eLocation-ID:
- p. W235-W245
- ISSN:
- 0305-1048
- Publisher:
- Oxford University Press
- Sponsoring Org:
- National Science Foundation
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Abstract -
Abstract Protein structure prediction is an important problem in bioinformatics and has been studied for decades. However, there are still few open-source comprehensive protein structure prediction packages publicly available in the field. In this paper, we present our latest open-source protein tertiary structure prediction system—MULTICOM2, an integration of template-based modeling (TBM) and template-free modeling (FM) methods. The template-based modeling uses sequence alignment tools with deep multiple sequence alignments to search for structural templates, which are much faster and more accurate than MULTICOM1. The template-free (ab initio or de novo) modeling uses the inter-residue distances predicted by DeepDist to reconstruct tertiary structure models without using any known structure as template. In the blind CASP14 experiment, the average TM-score of the models predicted by our server predictor based on the MULTICOM2 system is 0.720 for 58 TBM (regular) domains and 0.514 for 38 FM and FM/TBM (hard) domains, indicating that MULTICOM2 is capable of predicting good tertiary structures across the board. It can predict the correct fold for 76 CASP14 domains (95% regular domains and 55% hard domains) if only one prediction is made for a domain. The success rate is increased to 3% for both regular and hard domains if fivemore »
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Abstract Motivation Deep learning has revolutionized protein tertiary structure prediction recently. The cutting-edge deep learning methods such as AlphaFold can predict high-accuracy tertiary structures for most individual protein chains. However, the accuracy of predicting quaternary structures of protein complexes consisting of multiple chains is still relatively low due to lack of advanced deep learning methods in the field. Because interchain residue–residue contacts can be used as distance restraints to guide quaternary structure modeling, here we develop a deep dilated convolutional residual network method (DRCon) to predict interchain residue–residue contacts in homodimers from residue–residue co-evolutionary signals derived from multiple sequence alignments of monomers, intrachain residue–residue contacts of monomers extracted from true/predicted tertiary structures or predicted by deep learning, and other sequence and structural features.
Results Tested on three homodimer test datasets (Homo_std dataset, DeepHomo dataset and CASP-CAPRI dataset), the precision of DRCon for top L/5 interchain contact predictions (L: length of monomer in a homodimer) is 43.46%, 47.10% and 33.50% respectively at 6 Å contact threshold, which is substantially better than DeepHomo and DNCON2_inter and similar to Glinter. Moreover, our experiments demonstrate that using predicted tertiary structure or intrachain contacts of monomers in the unbound state as input, DRCon still performs well, even thoughmore »
Availability and implementation The source code of DRCon is available at https://github.com/jianlin-cheng/DRCon. The datasets are available at https://zenodo.org/record/5998532#.YgF70vXMKsB.
Supplementary information Supplementary data are available at Bioinformatics online.
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Abstract Motivation Deep learning has become the dominant technology for protein contact prediction. However, the factors that affect the performance of deep learning in contact prediction have not been systematically investigated. Results We analyzed the results of our three deep learning-based contact prediction methods (MULTICOM-CLUSTER, MULTICOM-CONSTRUCT and MULTICOM-NOVEL) in the CASP13 experiment and identified several key factors [i.e. deep learning technique, multiple sequence alignment (MSA), distance distribution prediction and domain-based contact integration] that influenced the contact prediction accuracy. We compared our convolutional neural network (CNN)-based contact prediction methods with three coevolution-based methods on 75 CASP13 targets consisting of 108 domains. We demonstrated that the CNN-based multi-distance approach was able to leverage global coevolutionary coupling patterns comprised of multiple correlated contacts for more accurate contact prediction than the local coevolution-based methods, leading to a substantial increase of precision by 19.2 percentage points. We also tested different alignment methods and domain-based contact prediction with the deep learning contact predictors. The comparison of the three methods showed deeper sequence alignments and the integration of domain-based contact prediction with the full-length contact prediction improved the performance of contact prediction. Moreover, we demonstrated that the domain-based contact prediction based on a novel ab initio approachmore »
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Abstract Motivation The success of genome sequencing techniques has resulted in rapid explosion of protein sequences. Collections of multiple homologous sequences can provide critical information to the modeling of structure and function of unknown proteins. There are however no standard and efficient pipeline available for sensitive multiple sequence alignment (MSA) collection. This is particularly challenging when large whole-genome and metagenome databases are involved. Results We developed DeepMSA, a new open-source method for sensitive MSA construction, which has homologous sequences and alignments created from multi-sources of whole-genome and metagenome databases through complementary hidden Markov model algorithms. The practical usefulness of the pipeline was examined in three large-scale benchmark experiments based on 614 non-redundant proteins. First, DeepMSA was utilized to generate MSAs for residue-level contact prediction by six coevolution and deep learning-based programs, which resulted in an accuracy increase in long-range contacts by up to 24.4% compared to the default programs. Next, multiple threading programs are performed for homologous structure identification, where the average TM-score of the template alignments has over 7.5% increases with the use of the new DeepMSA profiles. Finally, DeepMSA was used for secondary structure prediction and resulted in statistically significant improvements in the Q3 accuracy. It is notedmore »
