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Register a new userDistance-based Protein Folding Powered by Deep Learning
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Jinbo Xu
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Contact-assisted protein folding has made very good progress, but two challenges remain. One is accurate contact prediction for proteins lack of many sequence homologs and the other is that time-consuming folding simulation is often needed to predict good 3D models from predicted contacts. We show that protein distance matrix can be predicted well by deep learning and then directly used to construct 3D models without folding simulation at all. Using distance geometry to construct 3D models from our predicted distance matrices, we successfully folded 21 of the 37 CASP12 hard targets with a median family size of 58 effective sequence homologs within 4 hours on a Linux computer of 20 CPUs. In contrast, contacts predicted by direct coupling analysis (DCA) cannot fold any of them in the absence of folding simulation and the best CASP12 group folded 11 of them by integrating predicted contacts into complex, fragment-based folding simulation. The rigorous experimental validation on 15 CASP13 targets show that among the 3 hardest targets of new fold our distance-based folding servers successfully folded 2 large ones with <150 sequence homologs while the other servers failed on all three, and that our ab initio folding server also predicted the best, high-quality 3D model for a large homology modeling target. Further experimental validation in CAMEO shows that our ab initio folding server predicted correct fold for a membrane protein of new fold with 200 residues and 229 sequence homologs while all the other servers failed. These results imply that deep learning offers an efficient and accurate solution for ab initio folding on a personal computer.
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Significant progress in computer hardware and software have enabled molecular dynamics (MD) simulations to model complex biological phenomena such as protein folding. However, enabling MD simulations to access biologically relevant timescales (e.g., beyond milliseconds) still remains challenging. These limitations include (1) quantifying which set of states have already been (sufficiently) sampled in an ensemble of MD runs, and (2) identifying novel states from which simulations can be initiated to sample rare events (e.g., sampling folding events). With the recent success of deep learning and artificial intelligence techniques in analyzing large datasets, we posit that these techniques can also be used to adaptively guide MD simulations to model such complex biological phenomena. Leveraging our recently developed unsupervised deep learning technique to cluster protein folding trajectories into partially folded intermediates, we build an iterative workflow that enables our generative model to be coupled with all-atom MD simulations to fold small protein systems on emerging high performance computing platforms. We demonstrate our approach in folding Fs-peptide and the $betabetaalpha$ (BBA) fold, FSD-EY. Our adaptive workflow enables us to achieve an overall root-mean squared deviation (RMSD) to the native state of 1.6$~AA$ and 4.4~$AA$ respectively for Fs-peptide and FSD-EY. We also highlight some emerging challenges in the context of designing scalable workflows when data intensive deep learning techniques are coupled to compute intensive MD simulations.
Computational elucidation of membrane protein (MP) structures is challenging partially due to lack of sufficient solved structures for homology modeling. Here we describe a high-throughput deep transfer learning method that first predicts MP contacts by learning from non-membrane proteins (non-MPs) and then predicting three-dimensional structure models using the predicted contacts as distance restraints. Tested on 510 non-redundant MPs, our method has contact prediction accuracy at least 0.18 better than existing methods, predicts correct folds for 218 MPs (TMscore at least 0.6), and generates three-dimensional models with RMSD less than 4 Angstrom and 5 Angstrom for 57 and 108 MPs, respectively. A rigorous blind test in the continuous automated model evaluation (CAMEO) project shows that our method predicted high-resolution three-dimensional models for two recent test MPs of 210 residues with RMSD close to 2 Angstrom. We estimated that our method could predict correct folds for between 1,345 and 1,871 reviewed human multi-pass MPs including a few hundred new folds, which shall facilitate the discovery of drugs targeting at membrane proteins.
The intricate three-dimensional geometries of protein tertiary structures underlie protein function and emerge through a folding process from one-dimensional chains of amino acids. The exact spatial sequence and configuration of amino acids, the biochemical environment and the temporal sequence of distinct interactions yield a complex folding process that cannot yet be easily tracked for all proteins. To gain qualitative insights into the fundamental mechanisms behind the folding dynamics and generic features of the folded structure, we propose a simple model of structure formation that takes into account only fundamental geometric constraints and otherwise assumes randomly paired connections. We find that despite its simplicity, the model results in a network ensemble consistent with key overall features of the ensemble of Protein Residue Networks we obtained from more than 1000 biological protein geometries as available through the Protein Data Base. Specifically, the distribution of the number of interaction neighbors a unit (amino acid) has, the scaling of the structures spatial extent with chain length, the eigenvalue spectrum and the scaling of the smallest relaxation time with chain length are all consistent between model and real proteins. These results indicate that geometric constraints alone may already account for a number of generic features of protein tertiary structures.
Accurate protein structure prediction from amino-acid sequences is critical to better understanding the protein function. Recent advances in this area largely benefit from more precise inter-residue distance and orientation predictions, powered by deep neural networks. However, the structure optimization procedure is still dominated by traditional tools, e.g. Rosetta, where the structure is solved via minimizing a pre-defined statistical energy function (with optional prediction-based restraints). Such energy function may not be optimal in formulating the whole conformation space of proteins. In this paper, we propose a fully-differentiable approach for protein structure optimization, guided by a data-driven generative network. This network is trained in a denoising manner, attempting to predict the correction signal from corrupted distance matrices between Ca atoms. Once the network is well trained, Langevin dynamics based sampling is adopted to gradually optimize structures from random initialization. Extensive experiments demonstrate that our EBM-Fold approach can efficiently produce high-quality decoys, compared against traditional Rosetta-based structure optimization routines.
Energy landscape theory describes how a full-length protein can attain its native fold after sampling only a tiny fraction of all possible structures. Although protein folding is now understood to be concomitant with synthesis on the ribosome there have been few attempts to modify energy landscape theory by accounting for cotranslational folding. This paper introduces a model for cotranslational folding that leads to a natural definition of a nested energy landscape. By applying concepts drawn from submanifold differential geometry the dynamics of protein folding on the ribosome can be explored in a quantitative manner and conditions on the nested potential energy landscapes for a good cotranslational folder are obtained. A generalisation of diffusion rate theory using van Kampens technique of composite stochastic processes is then used to account for entropic contributions and the effects of variable translation rates on cotranslational folding. This stochastic approach agrees well with experimental results and Hamiltionian formalism in the deterministic limit.
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