Plug & play directed evolution of proteins with gradient-based discrete MCMC

Journal Article · 24 April 2023 · Machine Learning: Science and Technology

DOI: https://doi.org/10.1088/2632-2153/accacd · OSTI ID:1971401

Emami, Patrick ; Perreault, Aidan; Law, Jeffrey; Biagioni, David; St. John, Peter

Abstract A long-standing goal of machine-learning-based protein engineering is to accelerate the discovery of novel mutations that improve the function of a known protein. We introduce a sampling framework for evolving proteins in silico that supports mixing and matching a variety of unsupervised models, such as protein language models, and supervised models that predict protein function from sequence. By composing these models, we aim to improve our ability to evaluate unseen mutations and constrain search to regions of sequence space likely to contain functional proteins. Our framework achieves this without any model fine-tuning or re-training by constructing a product of experts distribution directly in discrete protein space. Instead of resorting to brute force search or random sampling, which is typical of classic directed evolution, we introduce a fast Markov chain Monte Carlo sampler that uses gradients to propose promising mutations. We conduct in silico directed evolution experiments on wide fitness landscapes and across a range of different pre-trained unsupervised models, including a 650 M parameter protein language model. Our results demonstrate an ability to efficiently discover variants with high evolutionary likelihood as well as estimated activity multiple mutations away from a wild type protein, suggesting our sampler provides a practical and effective new paradigm for machine-learning-based protein engineering.

• Research Organization: National Renewable Energy Laboratory (NREL), Golden, CO (United States)
• Sponsoring Organization: USDOE; USDOE Laboratory Directed Research and Development (LDRD) Program; USDOE Office of Energy Efficiency and Renewable Energy (EERE); USDOE Office of Energy Efficiency and Renewable Energy (EERE), Office of Sustainable Transportation. Bioenergy Technologies Office (BETO); USDOE Office of Science (SC)
• Grant/Contract Number: AC05-00OR22725; AC36-08GO28308
• OSTI ID: 1971401
• Report Number(s): NREL/JA-2C00-84201
• Journal Information: Machine Learning: Science and Technology, Journal Name: Machine Learning: Science and Technology Journal Issue: 2 Vol. 4; ISSN 2632-2153
• Publisher: IOP PublishingCopyright Statement
• Country of Publication: United Kingdom
• Language: English