Conformational Rank Conditioned Committees for Machine Learning-Assisted Directed Evolution

Abstract: Machine Learning-assisted directed evolution (MLDE) is a powerful tool for efficiently navigating antibody fitness landscapes. Many structure-aware MLDE pipelines rely on a single conformation or a single committee across all conformations, limiting their ability to separate conformational uncertainty from epistemic uncertainty. Here, we introduce a rank -conditioned committee (RCC) framework that leverages ranked conformations to assign a deep neural network committee per rank. This design enables a principled separation between epistemic uncertainty and conformational uncertainty. We validate our approach on SARS-CoV-2 antibody docking, demonstrating significant improvements over baseline strategies. Our results offer a scalable route for therapeutic antibody discovery while directly addressing the challenge of modeling conformational uncertainty.