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Or is the catalytic process more like a maze of forest trails? Enzyme mechanisms are typically presented as a linear (or circular) sequence of chemical steps, and most mechanistic studies aim to identify \u201cthe\u201d correct catalytic pathway. Alternative proposals are often pitted against one another and sometimes fiercely debated. In this paper, we consider the possibility that the reaction mechanism space accessible to enzyme active sites is more diverse than commonly recognized. This mechanistic space can be conveniently represented as a graph, where nodes correspond to active-site configurations (reactants, intermediates, or products) and edges denote catalytic steps transforming one configuration into another. We show that it is possible to generate alternative mechanism proposals, which take into account the 3D coordinates of the active site and known catalytic rules, for more than half of a test set of 25 enzymes. These findings hint at a previously unexplored facet of enzyme catalysis and underscore the need for the systematic exploration of the complete reactional space in computational studies of enzyme mechanisms.<\/jats:p>","DOI":"10.1063\/5.0288283","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T11:34:25Z","timestamp":1759318465000},"update-policy":"https:\/\/doi.org\/10.1063\/aip-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Off the beaten (catalytic) path: Charting the mechanistic space of enzyme reactions"],"prefix":"10.1063","volume":"163","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2533-1231","authenticated-orcid":false,"given":"Ant\u00f3nio J. 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