Evolution-Inspired Loss Functions for Protein Representation Learning

Chengyue Gong, Adam Klivans, James Madigan Loy, Tianlong Chen, qiang liu, Daniel Jesus Diaz

Track: Machine learning: computational method and/or computational results

Keywords: protein enginerring, single-point mutation effect prediction

Abstract:

AI-based frameworks for protein engineering use self-supervised learning (SSL) to obtain representations for downstream biological predictions. The most common training objective for these methods is wildtype accuracy: given a sequence or structure where a wildtype residue has been masked, predict the missing amino acid. Wildtype accuracy, however, does not align with the primary goal of protein engineering, which is to suggest a {\em mutation} rather than to identify what already appears in nature.

Here we present Evolutionary Ranking (EvoRank), a training objective that incorporates evolutionary information derived from multiple sequence alignments (MSAs) to learn more diverse protein representations. EvoRank corresponds to ranking amino-acid likelihoods in the probability distribution induced by an MSA. This objective forces models to learn the underlying evolutionary dynamics of a protein.

Across a variety of phenotypes and datasets, we demonstrate that EvoRank leads to dramatic improvements in zero-shot performance and can compete with models fine-tuned on experimental data. This is particularly important in protein engineering, where it is expensive to obtain data for fine-tuning.

Submission Number: 42