Biology subjects

Bremer, B. J.

Publications and source records attributed to Bremer, B. J..

2 recordsLinked to original sources

bioRxiv2023

Self-driving laboratories to autonomously navigate the protein fitness landscape

Protein engineering has nearly limitless applications across chemistry, energy, and medicine, but creating new proteins with improved or novel functions remains slow, labor-intensive, and inefficient. In this work, we present the Self-driving Autonomous Machines for Protein Landscape Exploration (SAMPLE) platform for fully autonomous protein engineering. SAMPLE is driven by an intelligent agent that learns protein sequence-function relationships, designs new proteins, and sends designs to a fully automated robotic system that experimentally tests designed proteins and provides feedback to improve the agents understanding of the system. We deployed four SAMPLE agents with the goal of engineering glycoside hydrolase enzymes with enhanced thermal tolerance. Despite showing individual differences in their search behavior, all four agents quickly converged on thermostable enzymes that were at least 12 {degrees}C more stable than the starting sequences. Self-driving laboratories automate and accelerate the scientific discovery process and hold great potential for the fields of protein engineering and synthetic biology.

synthetic biology↗

bioRxiv2020

Inferring protein sequence-function relationships with large-scale positive-unlabeled learning

Machine learning can infer how protein sequence maps to function without requiring a detailed understanding of the underlying physical or biological mechanisms. Its challenging to apply existing supervised learning frameworks to large-scale experimental data generated by deep mutational scanning (DMS) and related methods. DMS data often contain high dimensional and correlated sequence variables, experimental sampling error and bias, and the presence of missing data. Importantly, most DMS data do not contain examples of negative sequences, making it challenging to directly estimate how sequence affects function. Here, we develop a positive-unlabeled (PU) learning framework to infer sequence-function relationships from large-scale DMS data. Our PU learning method displays excellent predictive performance across ten large-scale sequence-function data sets, representing proteins of different folds, functions, and library types. The estimated parameters pinpoint key residues that dictate protein structure and function. Finally, we apply our statistical sequence-function model to design highly stabilized enzymes.

bioinformatics↗