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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/.

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 »of broader biomedical community for template-based protein structure and function modelling.

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Sequence-based contact prediction has shown considerable promise in assisting non-homologous structure modeling, but it often requires many homologous sequences and a sufficient number of correct contacts to achieve correct folds. Here, we developed a method, C-QUARK, that integrates multiple deep-learning and coevolution-based contact-maps to guide the replica-exchange Monte Carlo fragment assembly simulations. The method was tested on 247 non-redundant proteins, where C-QUARK could fold 75% of the cases with TM-scores (template-modeling scores) ≥0.5, which was 2.6 times more than that achieved by QUARK. For the 59 cases that had either low contact accuracy or few homologous sequences, C-QUARK correctly folded 6 times more proteins than other contact-based folding methods. C-QUARK was also tested on 64 free-modeling targets from the 13th CASP (critical assessment of protein structure prediction) experiment and had an average GDT_TS (global distance test) score that was 5% higher than the best CASP predictors. These data demonstrate, in a robust manner, the progress in modeling non-homologous protein structures using low-accuracy and sparse contact-map predictions.

The topology of protein folds can be specified by the inter-residue contact-maps and accurate contact-map prediction can help ab initio structure folding. We developed TripletRes to deduce protein contact-maps from discretized distance profiles by end-to-end training of deep residual neural-networks. Compared to previous approaches, the major advantage of TripletRes is in its ability to learn and directly fuse a triplet of coevolutionary matrices extracted from the whole-genome and metagenome databases and therefore minimize the information loss during the course of contact model training. TripletRes was tested on a large set of 245 non-homologous proteins from CASP 11&12 and CAMEO experiments and outperformed other top methods from CASP12 by at least 58.4% for the CASP 11&12 targets and 44.4% for the CAMEO targets in the top- L long-range contact precision. On the 31 FM targets from the latest CASP13 challenge, TripletRes achieved the highest precision (71.6%) for the top- L /5 long-range contact predictions. It was also shown that a simple re-training of the TripletRes model with more proteins can lead to further improvement with precisions comparable to state-of-the-art methods developed after CASP13. These results demonstrate a novel efficient approach to extend the power of deep convolutional networks for high-accuracy medium-more »and long-range protein contact-map predictions starting from primary sequences, which are critical for constructing 3D structure of proteins that lack homologous templates in the PDB library.« less