EnzyControl: Adding Functional and Substrate-Specific Control for Enzyme Backbone Generation

TL;DR

EnzyControl is a novel method that enables substrate-specific and functional control in enzyme backbone generation, improving designability and catalytic efficiency over existing models.

Contribution

We introduce EnzyControl, a new approach that incorporates substrate-awareness into enzyme backbone generation using a modular adapter and a curated enzyme-substrate dataset.

Findings

Achieves 13% improvement in designability

Enhances catalytic efficiency by 13%

Outperforms baseline models on structural and functional metrics

Abstract

Designing enzyme backbones with substrate-specific functionality is a critical challenge in computational protein engineering. Current generative models excel in protein design but face limitations in binding data, substrate-specific control, and flexibility for de novo enzyme backbone generation. To address this, we introduce EnzyBind, a dataset with 11,100 experimentally validated enzyme-substrate pairs specifically curated from PDBbind. Building on this, we propose EnzyControl, a method that enables functional and substrate-specific control in enzyme backbone generation. Our approach generates enzyme backbones conditioned on MSA-annotated catalytic sites and their corresponding substrates, which are automatically extracted from curated enzyme-substrate data. At the core of EnzyControl is EnzyAdapter, a lightweight, modular component integrated into a pretrained motif-scaffolding model, allowing it to become substrate-aware. A two-stage training paradigm further refines the model's ability to generate accurate and functional enzyme structures. Experiments show that our EnzyControl achieves the best performance across structural and functional metrics on EnzyBind and EnzyBench benchmarks, with particularly notable improvements of 13\% in designability and 13\% in catalytic efficiency compared to the baseline models. The code is released at https://github.com/Vecteur-libre/EnzyControl.