Simulation-based Protein Engineering with Transferable Implicit Transfer Operators

forthcoming

Minute changes in proteins—such as a single amino acid substitution—can profoundly impact cellular function. A computational model capable of systematically mapping the relationship between protein sequences, their dynamics, and their interactions with other biomolecules would revolutionize biology and enable rational, physics-informed bioengineering applications. SPETITO outlines the methodological foundations for such a framework. Recent advances in deep generative AI (GenAI) have enabled surrogate methods for efficient molecular dynamics (MD) simulations, tackling the challenge of sampling rare events and conformational transitions. The PI co-developed groundbreaking methods—Boltzmann Generators (BG) and Implicit Transfer Operators (ITO)— that enable the study of conformational changes, protein folding, and prediction of experiments five orders of magnitude faster than MD. However, these methods cannot generalize across molecular systems nor scale to larger molecules, severely limiting their utility. To address this, we propose developing and disseminating transformative technologies through widely accessible software: • A transferable ITO (TransITO) model that captures universal protein physics, enabling rapid sampling with microsecond-time-steps for any protein system without requiring system-specific training data. • A ‘protein sequence gradient’-based optimization framework, enabling efficient exploration and optimization of protein sequence space for targeted functional outcomes. • An automated protocol for protein design that integrates multiple thermodynamic constraints, facilitating the rational engineering of proteins with desired properties. Beyond turbo-charged atomic-resolution insights into biophysics, TransITO will enable rational, physics-informed protein engineering. With experimental collaborators, we will apply TransITO to vaccine development, to accelerate therapeutic design for infectious diseases.