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Register a new userDeepDriveMD: Deep-Learning Driven Adaptive Molecular Simulations for Protein Folding
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Shantenu Jha
Publication date
2019
fields
Informatics Engineering
and research's language is
English
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Simulations of biological macromolecules play an important role in understanding the physical basis of a number of complex processes such as protein folding. Even with increasing computational power and evolution of specialized architectures, the ability to simulate protein folding at atomistic scales still remains challenging. This stems from the dual aspects of high dimensionality of protein conformational landscapes, and the inability of atomistic molecular dynamics (MD) simulations to sufficiently sample these landscapes to observe folding events. Machine learning/deep learning (ML/DL) techniques, when combined with atomistic MD simulations offer the opportunity to potentially overcome these limitations by: (1) effectively reducing the dimensionality of MD simulations to automatically build latent representations that correspond to biophysically relevant reaction coordinates (RCs), and (2) driving MD simulations to automatically sample potentially novel conformational states based on these RCs. We examine how coupling DL approaches with MD simulations can fold small proteins effectively on supercomputers. In particular, we study the computational costs and effectiveness of scaling DL-coupled MD workflows by folding two prototypical systems, viz., Fs-peptide and the fast-folding variant of the villin head piece protein. We demonstrate that a DL driven MD workflow is able to effectively learn latent representations and drive adaptive simulations. Compared to traditional MD-based approaches, our approach achieves an effective performance gain in sampling the folded states by at least 2.3x. Our study provides a quantitative basis to understand how DL driven MD simulations, can lead to effective performance gains and reduced times to solution on supercomputing resources.
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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.
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.
Machine-learning models that learn from data to predict how protein sequence encodes function are emerging as a useful protein engineering tool. However, when using these models to suggest new protein designs, one must deal with the vast combinatorial complexity of protein sequences. Here, we review how to use a sequence-to-function machine-learning surrogate model to select sequences for experimental measurement. First, we discuss how to select sequences through a single round of machine-learning optimization. Then, we discuss sequential optimization, where the goal is to discover optimized sequences and improve the model across multiple rounds of training, optimization, and experimental measurement.
In spite of decades of research, much remains to be discovered about folding: the detailed structure of the initial (unfolded) state, vestigial folding instructions remaining only in the unfolded state, the interaction of the molecule with the solvent, instantaneous power at each point within the molecule during folding, the fact that the process is stable in spite of myriad possible disturbances, potential stabilization of trajectory by chaos, and, of course, the exact physical mechanism (code or instructions) by which the folding process is specified in the amino acid sequence. Simulations based upon microscopic physics have had some spectacular successes and continue to improve, particularly as super-computer capabilities increase. The simulations, exciting as they are, are still too slow and expensive to deal with the enormous number of molecules of interest. In this paper, we introduce an approximate model based upon physics, empirics, and information science which is proposed for use in machine learning applications in which very large numbers of sub-simulations must be made. In particular, we focus upon machine learning applications in the learning phase and argue that our model is sufficiently close to the physics that, in spite of its approximate nature, can facilitate stepping through machine learning solutions to explore the mechanics of folding mentioned above. We particularly emphasize the exploration of energy flow (power) within the molecule during folding, the possibility of energy scale invariance (above a threshold), vestigial information in the unfolded state as attractive targets for such machine language analysis, and statistical analysis of an ensemble of folding micro-steps.
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.
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