Comparing structural ensembles with DiffNets helps explain the activation mechanism of the SARS-CoV-2 protein NSP16

Understanding the structural determinants of a protein’s biochemical properties, such as enzymatic activity, is a major challenge in biology and medicine. Comparing computer simulations of protein variants with different biochemical properties is an increasingly powerful means to drive progress. However, success often hinges on dimensionality reduction algorithms for simplifying the complex ensemble of structures each variant adopts. Unfortunately, common algorithms rely on potentially misleading assumptions about what structural features are important, such as emphasizing larger geometric changes over smaller ones.