An automated transition state search and its application to diverse types of organic reactions

Leif D. Jacobson, Art D. Bochevarov, Mark A. Watson, Thomas F. Hughes, David Rinaldo, Stephan Ehrlich, Thomas B. Steinbrecher, S. Vaitheeswaran, Dean M. Philipp, Mathew D. Halls, and Richard A. Friesner (2017)

Highlighted by Jan Jensen

Copyright 2017 American Chemical Society

Finding transition states remains one of the most labor intensive pursuits in computational chemistry.  While interpolation methods are becoming increasingly robust, they usually require that the atom order for reactant and product are identical (atom mapping) and can be sensitive the starting conformations and relative orientation in case of bi-molecular reactions.  Furthermore, one still has to check whether the right TS is found and formulate a strategy if it is not.  All these things to do not immediately lend themselves to automation but this paper proposes solutions for all these problems.

In particular the paper offers a very elegant solution for the atom mapping problem: bonds are broken in both reactants and products until the connectivity of the fragments are identical after which the atoms in the fragments can be easily matched. Both the comparison and atom mapping of fragments can be easily done with modern cheminformatics toolkits such as RDKit using canonical smiles and  maximum common substructure searchers (after atom order and charge has been removed).  Cases where this fails due to equivalent atoms (e.g. the hydrogens in a methylene group) can then be dealt with by searching for the solution with the lowest RSMD between reactant and product.

The study focussed on relatively small and rigid molecules and issues due to multiple conformations is left for a future publication.

This work is licensed under a Creative Commons Attribution 4.0 International License.