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 for exploring the single-state potential energy surfaces and conical intersection seam spaces of a wide range of molecules. Despite 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 explicit exploration of a comparatively large Crystal configurational subspace, while relaxing the other degrees of freedom in the system. The new Crystal algorithm is applied to reaction discovery of bilirubin and donor-acceptor Stenhouse adducts, a next-generation class of molecular photoswitches, in the vacuum and the aqueous solution. In order to make this possible, we designed an automatic and systematic workflow in Crystal to discover and characterize new minima and low-energy reaction pathways in these complex systems. Our findings reveal the algorithm's effectiveness in quickly exploring the configuration space and uncovering new product minima that are kinetically accessible, which provides new insights into the intricate chemical reactivities of these molecules and the roles of molecular environments on the reaction pathways. The results underscore the promising potential of parallelized global exploration methods for reaction discovery in biomolecular systems.