Development of Parallel On-the-Fly Crystal Algorithm for Reaction Discovery in Large and Complex Molecular Systems

The parallel on-the-fly Crystal algorithm is a new, efficient global search algorithm that has found utility in exploring the single-state potential energy surfaces and conical intersection seam spaces of a wide range of molecules in the gas phase. Despite its major developments, its application to complex molecular systems, especially in the condensed phase, remains challenging due to the high dimensionality of the configurational space. In this work, we address this challenge and extend its applicability to the reaction discovery of large, complex molecular photoswitches in the condensed phase. This is achieved by improved search algorithms that facilitate the exploration of a comparatively large Crystal configurational subspace while relaxing the other degrees of freedom. The new Crystal algorithm is applied to bilirubin and a next-generation class of molecular photoswitches in the vacuum and the aqueous solution environment in a quantum mechanics/molecular mechanics (QM/MM) setting. We designed an automatic and systematic workflow to discover previously unreported minima and low-energy reaction pathways and analyze them with a focus on the low-energy spectrum. Our findings reveal the algorithm's effectiveness in quickly exploring the configuration space, uncovering new product minima that are kinetically accessible, which provides new insights into the intricate chemical reactivities of these molecules. The results underscore the promising potential of parallelized global exploration methods in reaction discovery in biomolecular systems.