Dataset Information

Data-driven supervised learning of a viral protease specificity landscape from deep sequencing and molecular simulations.

ABSTRACT: Biophysical interactions between proteins and peptides are key determinants of molecular recognition specificity landscapes. However, an understanding of how molecular structure and residue-level energetics at protein-peptide interfaces shape these landscapes remains elusive. We combine information from yeast-based library screening, next-generation sequencing, and structure-based modeling in a supervised machine learning approach to report the comprehensive sequence-energetics-function mapping of the specificity landscape of the hepatitis C virus (HCV) NS3/4A protease, whose function-site-specific cleavages of the viral polyprotein-is a key determinant of viral fitness. We screened a library of substrates in which five residue positions were randomized and measured cleavability of ?30,000 substrates (?1% of the library) using yeast display and fluorescence-activated cell sorting followed by deep sequencing. Structure-based models of a subset of experimentally derived sequences were used in a supervised learning procedure to train a support vector machine to predict the cleavability of 3.2 million substrate variants by the HCV protease. The resulting landscape allows identification of previously unidentified HCV protease substrates, and graph-theoretic analyses reveal extensive clustering of cleavable and uncleavable motifs in sequence space. Specificity landscapes of known drug-resistant variants are similarly clustered. The described approach should enable the elucidation and redesign of specificity landscapes of a wide variety of proteases, including human-origin enzymes. Our results also suggest a possible role for residue-level energetics in shaping plateau-like functional landscapes predicted from viral quasispecies theory.

SUBMITTER: Pethe MA

PROVIDER: S-EPMC6320525 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

Data-driven supervised learning of a viral protease specificity landscape from deep sequencing and molecular simulations.

Pethe Manasi A MA Rubenstein Aliza B AB Khare Sagar D SD

Proceedings of the National Academy of Sciences of the United States of America 20181226 1

Biophysical interactions between proteins and peptides are key determinants of molecular recognition specificity landscapes. However, an understanding of how molecular structure and residue-level energetics at protein-peptide interfaces shape these landscapes remains elusive. We combine information from yeast-based library screening, next-generation sequencing, and structure-based modeling in a supervised machine learning approach to report the comprehensive sequence-energetics-function mapping ...[more]

PMID: 30587591

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Project description:Computational modelling of physical and biochemical processes has emerged as a means of evaluating medical devices, offering new insights that explain current performance, inform future designs and even enable personalized use. Yet resource limitations force one to compromise with reduced order computational models and idealized assumptions that yield either qualitative descriptions or approximate, quantitative solutions to problems of interest. Considering endovascular drug delivery as an exemplary scenario, we used a supervised machine learning framework to process data generated from low fidelity coarse meshes and predict high fidelity solutions on refined mesh configurations. We considered two models simulating drug delivery to the arterial wall: (i) two-dimensional drug-coated balloons and (ii) three-dimensional drug-eluting stents. Simulations were performed on computational mesh configurations of increasing density. Supervised learners based on Gaussian process modelling were constructed from combinations of coarse mesh setting solutions of drug concentrations and nearest neighbourhood distance information as inputs, and higher fidelity mesh solutions as outputs. These learners were then used as computationally inexpensive surrogates to extend predictions using low fidelity information to higher levels of mesh refinement. The cross-validated, supervised learner-based predictions improved fidelity as compared with computational simulations performed at coarse level meshes--a result consistent across all outputs and computational models considered. Supervised learning on coarse mesh solutions can augment traditional physics-based modelling of complex physiologic phenomena. By obtaining efficient solutions at a fraction of the computational cost, this framework has the potential to transform how modelling approaches can be applied in the evaluation of medical technologies and their real-time administration in an increasingly personalized fashion.

Dataset Information

Data-driven supervised learning of a viral protease specificity landscape from deep sequencing and molecular simulations.

Publications

Data-driven supervised learning of a viral protease specificity landscape from deep sequencing and molecular simulations.

Similar Datasets

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