In an interdisciplinary collaboration, the Martin and Butts labs modeled and analyzed every documented variant of the SARS-CoV-2 main protease during the first year of the pandemic.  Most of the news about COVID variants has focused on the spike protein, but the main protease has also changed over time in response to selective pressure, with implications for viral replication as well as the development of pharmaceuticals to counter it.  Understanding the impact of mutation on this protein will guide the design of mutation-resistant inhibitors.