Modeling enzyme temperature stability from sequence segment perspective

TL;DR

This paper introduces a new deep learning model, Segment Transformer, that predicts enzyme temperature stability from sequence segments, using a curated dataset, and successfully guides enzyme engineering with experimental validation.

Contribution

The paper presents a novel deep learning framework that incorporates segment-level representations for enzyme thermal stability prediction, addressing data limitations and improving accuracy.

Findings

State-of-the-art prediction performance with RMSE of 24.03 and MAE of 18.09.

Successful enzyme engineering with 1.64-fold activity improvement.

Demonstrated effectiveness of segment-based modeling in enzyme thermal analysis.

Abstract

Developing enzymes with desired thermal properties is crucial for a wide range of industrial and research applications, and determining temperature stability is an essential step in this process. Experimental determination of thermal parameters is labor-intensive, time-consuming, and costly. Moreover, existing computational approaches are often hindered by limited data availability and imbalanced distributions. To address these challenges, we introduce a curated temperature stability dataset designed for model development and benchmarking in enzyme thermal modeling. Leveraging this dataset, we present the \textit{Segment Transformer}, a novel deep learning framework that enables efficient and accurate prediction of enzyme temperature stability. The model achieves state-of-the-art performance with an RMSE of 24.03, MAE of 18.09, and Pearson and Spearman correlations of 0.33, respectively. These results highlight the effectiveness of incorporating segment-level representations, grounded in the biological observation that different regions of a protein sequence contribute unequally to thermal behavior. As a proof of concept, we applied the Segment Transformer to guide the engineering of a cutinase enzyme. Experimental validation demonstrated a 1.64-fold improvement in relative activity following heat treatment, achieved through only 17 mutations and without compromising catalytic function.