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DESTINI: A deep-learning approach to contact-driven protein structure prediction.

ABSTRACT: The amino acid sequence of a protein encodes the blueprint of its native structure. To predict the corresponding structural fold from the protein's sequence is one of most challenging problems in computational biology. In this work, we introduce DESTINI (deep structural inference for proteins), a novel computational approach that combines a deep-learning algorithm for protein residue/residue contact prediction with template-based structural modelling. For the first time, the significantly improved predictive ability is demonstrated in the large-scale tertiary structure prediction of over 1,200 single-domain proteins. DESTINI successfully predicts the tertiary structure of four times the number of "hard" targets (those with poor quality templates) that were previously intractable, viz, a "glass-ceiling" for previous template-based approaches, and also improves model quality for "easy" targets (those with good quality templates). The significantly better performance by DESTINI is largely due to the incorporation of better contact prediction into template modelling. To understand why deep-learning accomplishes more accurate contact prediction, systematic clustering reveals that deep-learning predicts coherent, native-like contact patterns compared to co-evolutionary analysis. Taken together, this work presents a promising strategy towards solving the protein structure prediction problem.

SUBMITTER: Gao M

PROVIDER: S-EPMC6401133 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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DESTINI: A deep-learning approach to contact-driven protein structure prediction.

Gao Mu M Zhou Hongyi H Skolnick Jeffrey J

Scientific reports 20190305 1

The amino acid sequence of a protein encodes the blueprint of its native structure. To predict the corresponding structural fold from the protein's sequence is one of most challenging problems in computational biology. In this work, we introduce DESTINI (deep structural inference for proteins), a novel computational approach that combines a deep-learning algorithm for protein residue/residue contact prediction with template-based structural modelling. For the first time, the significantly improv ...[more]

PMID: 30837676

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Project description:MotivationProtein contacts contain key information for the understanding of protein structure and function and thus, contact prediction from sequence is an important problem. Recently exciting progress has been made on this problem, but the predicted contacts for proteins without many sequence homologs is still of low quality and not very useful for de novo structure prediction.MethodThis paper presents a new deep learning method that predicts contacts by integrating both evolutionary coupling (EC) and sequence conservation information through an ultra-deep neural network formed by two deep residual neural networks. The first residual network conducts a series of 1-dimensional convolutional transformation of sequential features; the second residual network conducts a series of 2-dimensional convolutional transformation of pairwise information including output of the first residual network, EC information and pairwise potential. By using very deep residual networks, we can accurately model contact occurrence patterns and complex sequence-structure relationship and thus, obtain higher-quality contact prediction regardless of how many sequence homologs are available for proteins in question.ResultsOur method greatly outperforms existing methods and leads to much more accurate contact-assisted folding. Tested on 105 CASP11 targets, 76 past CAMEO hard targets, and 398 membrane proteins, the average top L long-range prediction accuracy obtained by our method, one representative EC method CCMpred and the CASP11 winner MetaPSICOV is 0.47, 0.21 and 0.30, respectively; the average top L/10 long-range accuracy of our method, CCMpred and MetaPSICOV is 0.77, 0.47 and 0.59, respectively. Ab initio folding using our predicted contacts as restraints but without any force fields can yield correct folds (i.e., TMscore>0.6) for 203 of the 579 test proteins, while that using MetaPSICOV- and CCMpred-predicted contacts can do so for only 79 and 62 of them, respectively. Our contact-assisted models also have much better quality than template-based models especially for membrane proteins. The 3D models built from our contact prediction have TMscore>0.5 for 208 of the 398 membrane proteins, while those from homology modeling have TMscore>0.5 for only 10 of them. Further, even if trained mostly by soluble proteins, our deep learning method works very well on membrane proteins. In the recent blind CAMEO benchmark, our fully-automated web server implementing this method successfully folded 6 targets with a new fold and only 0.3L-2.3L effective sequence homologs, including one β protein of 182 residues, one α+β protein of 125 residues, one α protein of 140 residues, one α protein of 217 residues, one α/β of 260 residues and one α protein of 462 residues. Our method also achieved the highest F1 score on free-modeling targets in the latest CASP (Critical Assessment of Structure Prediction), although it was not fully implemented back then.Availabilityhttp://raptorx.uchicago.edu/ContactMap/.

Dataset Information

DESTINI: A deep-learning approach to contact-driven protein structure prediction.

Publications

DESTINI: A deep-learning approach to contact-driven protein structure prediction.

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