Learning maximally spanning representations improves protein function annotation

Abstract Automated protein function annotation is a fundamental problem in computational biology, crucial for understanding the functional roles of proteins in biological processes, with broad implications in medicine and biotechnology. A persistent challenge in this problem is the imbalanced, long-tail distribution of available function annotations: a small set of well-studied function classes account for most annotated proteins, while many other classes have few annotated proteins, often due to investigative bias, experimental limitations, or intrinsic biases in protein evolution. As a result, existing machine learning models for protein function prediction tend to only optimize the prediction accuracy for well-studied function classes overrepresented in the training data, leading to poor accuracy for understudied functions. In this work, we develop MSRep, a novel deep learning-based protein function annotation framework designed to address this imbalance issue and improve annotation accuracy. MSRep is inspired by an intriguing phenomenon, called neural collapse (NC), commonly observed in high-accuracy deep neural networks used for classification tasks, where hidden representations in the final layer collapse to class-specific mean embeddings, while maintaining maximal inter-class separation. Given that NC consistently emerges across diverse architectures and tasks for high-accuracy models, we hypothesize that inducing NC structure in models trained on imbalanced data can enhance both prediction accuracy and generalizability. To achieve this, MSRep refines a pre-trained protein language model to produce NC-like representations by optimizing an NC-inspired loss function, which ensures that minority functions are equally represented in the embedding space as majority functions, in contrast to conventional classification methods whose embedding spaces are dominated by overrepresented classes. In evaluations across four protein function annotation tasks on the prediction of Enzyme Commission numbers, Gene3D codes, Pfam families, and Gene Ontology terms, MSRep demonstrates superior predictive performance for both well- and underrepresented classes, outperforming several state-of-the-art annotation tools. We anticipate that MSRep will enhance the annotation of understudied functions and novel, uncharacterized proteins, advancing future protein function studies and accelerating the discovery of new functional proteins. The source code of MSRep is available at https://github.com/luo-group/MSRep .