Mapping Enzymatic Catalysis using the Effective Fragment Molecular Orbital Method: Towards all ab initio Biochemistry

TL;DR

This paper introduces an extended EFMO method with a frozen domain approach, enabling efficient ab initio mapping of enzymatic reaction paths for large systems like chorismate mutase, without force fields.

Contribution

The authors develop a new EFMO-based method that combines a frozen domain approach with ab initio calculations, allowing automatic reaction path mapping of large biomolecules.

Findings

Reaction path mapped in less than four days using 80 cores.

Reaction barrier for chorismate mutase estimated at ~18-19 kcal/mol.

Method treats entire system ab initio without force fields.

Abstract

We extend the Effective Fragment Molecular Orbital (EFMO) method to the frozen domain approach where only the geometry of an active part is optimized, while the many-body polarization effects are considered for the whole system. The new approach efficiently mapped out the entire reaction path of chorismate mutase in less than four days using 80 cores on 20 nodes, where the whole system containing 2398 atoms is treated in the ab initio fashion without using any force fields. The reaction path is constructed automatically with the only assumption of defining the reaction coordinate a priori. We determine the reaction barrier of chorismate mutase to be $18.3\pm 3.5$ kcal mol$^{-1}$ for MP2/cc-pVDZ and $19.3\pm 3.6$ for MP2/cc-pVTZ in an ONIOM approach using EFMO-RHF/6-31G(d) for the high and low layers, respectively.