Spatially-Aware Diffraction Mapping Enables Fully Autonomous MicroED

In the hands of experts, microcrystal electron diffraction (microED, a 3D ED method) is a powerful tool for structural chemistry and chemical discovery. To expand the accessibility and utility of microED, we introduce Reciprocal Eyes (REyes), an autonomous, intelligent, and open-source platform that combines diffraction-based particle selection with real-time data processing to deliver crystal structures without human intervention. REyes spatially maps diffraction signal and autonomously selects crystallites of interest, relying on lattice-quality metrics to acquire and index high-resolution datasets from diverse compounds. Tested on four different transmission electron microscopes (TEMs), it consistently yields preliminary ab initio structural solutions from single crystallites of materials, peptides, metal complexes, and natural prod- ucts (NPs).