ProteinNPT: Improving Protein Property Prediction and Design with Non-Parametric Transformers.

Protein design holds immense potential for optimizing naturally occurring proteins, with broad applications in drug discovery, material design, and sustainability. However, computational methods for protein engineering are confronted with significant challenges, such as an expansive design space, sparse functional regions, and a scarcity of available labels. These issues are further exacerbated in practice by the fact most real-life design scenarios necessitate the simultaneous optimization of multiple properties. In this work, we introduce ProteinNPT, a non-parametric transformer variant tailored to protein sequences and particularly suited to label-scarce and multi-task learning settings. We first focus on the supervised fitness prediction setting and develop several cross-validation schemes which support robust performance assessment. We subsequently reimplement prior top-performing baselines, introduce several extensions of these baselines by integrating diverse branches of the protein engineering literature, and demonstrate that ProteinNPT consistently outperforms all of them across a diverse set of protein property prediction tasks. Finally, we demonstrate the value of our approach for iterative protein design across extensive in silico Bayesian optimization and conditional sampling experiments.

ProteinGym: Large-Scale Benchmarks for Protein Design and Fitness Prediction.

Predicting the effects of mutations in proteins is critical to many applications, from understanding genetic disease to designing novel proteins that can address our most pressing challenges in climate, agriculture and healthcare. Despite a surge in machine learning-based protein models to tackle these questions, an assessment of their respective benefits is challenging due to the use of distinct, often contrived, experimental datasets, and the variable performance of models across different protein families. Addressing these challenges requires scale. To that end we introduce ProteinGym, a large-scale and holistic set of benchmarks specifically designed for protein fitness prediction and design. It encompasses both a broad collection of over 250 standardized deep mutational scanning assays, spanning millions of mutated sequences, as well as curated clinical datasets providing high-quality expert annotations about mutation effects. We devise a robust evaluation framework that combines metrics for both fitness prediction and design, factors in known limitations of the underlying experimental methods, and covers both zero-shot and supervised settings. We report the performance of a diverse set of over 70 high-performing models from various subfields (eg., alignment-based, inverse folding) into a unified benchmark suite. We open source the corresponding codebase, datasets, MSAs, structures, model predictions and develop a user-friendly website that facilitates data access and analysis.