Self-driving laboratories to autonomously navigate the protein fitness landscape

Abstract 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 agent’s 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 °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.