Hierarchical generative modeling for the design of multi-component systems

Abstract

Abstract The functionality of catalysts, enzymes, and supramolecular assemblies emerges not from individual molecules alone, but from the subtle interplay between multiple components arranged in complex systems. Designing such systems is a grand challenge: the combinatorial explosion of possible chemical compositions and spatial arrangements makes brute-force exploration infeasible, while many current generative approaches remain limited to isolated molecules. In this work, we introduce a hierarchical generative optimization framework that overcomes this barrier by coupling a genetic algorithm for configurational search with a generative model for molecular design. This closed-loop approach enables simultaneous refinement of geometry and composition, efficiently steering discovery toward systems with targeted functionality. As a proof of concept, we design catalytic environments for the Claisen rearrangement of p-tolyl ether by optimizing surrounding components around a fixed reference transition-state geometry. Despite this constraint during the search phase, post-hoc validation via Climbing-Image Nudged Elastic Band calculations, with the environment held fixed, indicates a reduction of the activation barrier by about 30%. Beyond this example, the framework applies to systems in which a well-defined central structure is stabilized by non-covalently interacting components, such as supramolecular hosts and local catalytic environments.