Reaction-conditioned De Novo Enzyme Design with GENzyme

TL;DR

GENzyme is a novel reaction-conditioned enzyme design model that generates enzyme structures and catalytic pockets based on specific reactions, shifting from traditional binding-focused methods to a reaction-first approach for more accurate enzyme engineering.

Contribution

The paper introduces GENzyme, a three-stage, reaction-driven de novo enzyme design model that generates enzyme structures tailored to catalyze specific reactions, advancing enzyme design methodology.

Findings

GENzyme effectively designs enzyme structures for targeted reactions.

The model outperforms traditional binding-focused approaches in reaction-specific enzyme creation.

GENzyme's reaction-first approach improves biological relevance of designed enzymes.

Abstract

The introduction of models like RFDiffusionAA, AlphaFold3, AlphaProteo, and Chai1 has revolutionized protein structure modeling and interaction prediction, primarily from a binding perspective, focusing on creating ideal lock-and-key models. However, these methods can fall short for enzyme-substrate interactions, where perfect binding models are rare, and induced fit states are more common. To address this, we shift to a functional perspective for enzyme design, where the enzyme function is defined by the reaction it catalyzes. Here, we introduce \textsc{GENzyme}, a \textit{de novo} enzyme design model that takes a catalytic reaction as input and generates the catalytic pocket, full enzyme structure, and enzyme-substrate binding complex. \textsc{GENzyme} is an end-to-end, three-staged model that integrates (1) a catalytic pocket generation and sequence co-design module, (2) a pocket inpainting and enzyme inverse folding module, and (3) a binding and screening module to optimize and predict enzyme-substrate complexes. The entire design process is driven by the catalytic reaction being targeted. This reaction-first approach allows for more accurate and biologically relevant enzyme design, potentially surpassing structure-based and binding-focused models in creating enzymes capable of catalyzing specific reactions. We provide \textsc{GENzyme} code at https://github.com/WillHua127/GENzyme.