EnzymeCoT: De Novo Enzyme Design As A Chain Of Reasoning Coupled To A Chain Of Structure

Enzyme design aims to produce a sequence and a structure that together catalyse aspecified reaction. Existing conditional generators are given either a compact functional label, from which every decision is then made implicitly inside the sampler, or structural information such as catalytic sites or a motif, which de novo design is meant to produce rather than consume. Neither writes the design down in steps. We propose EnzymeCoT, which runs two coupled chains. From a de- scription of the reaction and a target length, a language model writes a chain of reasoning,the four remaining states of a five-state design record, moving from amechanistic prior through a catalytic core and an active site to a backbone and asequence. Each state names a wider part of the molecule than the last, and a masked discrete diffusion model over joint structure and sequence tokens is re- conditioned on it and asked to commit that part alone, so the written chain drives a chain of structure through the same five states. Where chain-of-thought in a lan- guage model feeds only the language model, each state here conditions the gen- erator directly, and at two depths: residue–position pairs at the input embedding, and the full token sequence by cross attention late in the denoiser. The corpus pairs enzymes with staged design rationales: deterministic code produces every claim and a verifier checks every sentence against it. Conditioned on the reaction and a target length, EnzymeCoT improves by 2.2 points of EC3 agreement on the strongest baseline evaluated under a specification that does not name the target class, and refolds closer to the reference backbone.