Motivation: The design of enzymes is as challenging as it is consequential for making chemical synthesis in medical and industrial applications more efficient, cost-effective and environmentally friendly. While several aspects of this complex problem are computationally assisted, the drafting of catalytic mechanisms, i.e. the specification of the chemical steps-A nd hence intermediate states-that the enzyme is meant to implement, is largely left to human expertise. The ability to capture specific chemistries of multistep catalysis in a fashion that enables its computational construction and design is therefore highly desirable and would equally impact the elucidation of existing enzymatic reactions whose mechanisms are unknown. Results: We use the mathematical framework of graph transformation to express the distinction between rules and reactions in chemistry. We derive about 1000 rules for amino acid side chain chemistry from the M-CSA database, a curated repository of enzymatic mechanisms. Using graph transformation, we are able to propose hundreds of hypothetical catalytic mechanisms for a large number of unrelated reactions in the Rhea database. We analyze these mechanisms to find that they combine in chemically sound fashion individual steps from a variety of known multistep mechanisms, showing that plausible novel mechanisms for catalysis can be constructed computationally.
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© 2021 The Author(s). Published by Oxford University Press.