Hierarchical generative modeling for the design of multi-component systems

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 confirm a 30% reduction in activation barrier. Beyond this example, our framework provides a general strategy for data-driven discovery of functional multi-component systems, opening the door to automated design of catalysts, enzyme active sites, and advanced materials. Scientific contribution. The study presents a closed loop generative framework that enables joint optimization of molecular components and their spatial organization in multi-component systems. The method moves generative molecular design beyond single molecules toward larger and more complex systems.