Graph transformation for enzymatic mechanisms

Abstract

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—and 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. Availability and implementation The source code of the initial prototype of our approach is available at https://github.com/Nojgaard/mechsearch Supplementary information Supplementary data are available at Bioinformatics online.

Representing Catalytic Mechanisms with Rule Composition

“…For the process used to prepare the M-CSA information for our approach, see. 12 Of these 600 M-CSA sequences, 435 have a unique mechanism and 100 have two mechanisms. Five M-CSA sequences are compatible with over 100 different mechanisms.…”

“…Because mathematical graphs are not two-dimensional structures, they simply represent connectivity. While the framework can, in principle, be augmented to include information about quantitative aspects, the current approach has already demonstrated theoretical and practical utility, ,− to which the present work seeks to add.…”

“…In particular, they can suggest the assignment of a mechanism to a reaction for which none is known. This differs from a previous approach that searched for a combination of elementary steps to achieve the desired outcome. While the previous approach can propose novel mechanisms by recombining steps, it suffers from the usual combinatorial explosion, confining it to rather short mechanisms.…”

EzMechanism: An Automated Tool to Propose Catalytic Mechanisms of Enzyme Reactions

“…The data in M-CSA is unique in its scope and breadth, and it has been used by ourselves and others to understand enzyme function and evolution [27][28][29][30] . Notably, we would like to highlight the work of Jakob Anderson and colleagues 14 , which used M-CSA data to test a new program they created that is able to perform multi-step chemical reactions in silico using graph transformation. For this, and independently from the work described in the present paper, they built a set of catalytic rules that are conceptually similar to our own "single-step" rules.…”

“…EzMechanism is the first computational method that is able to come up with potential enzyme mechanisms for a given 3D structure of an active site (we discuss a related knowledge-based method 14 developed independently in the online methods). We show that the software is efficient at searching the catalytic space and find productive paths between the reactants and products of enzyme reactions.…”