Mapping enzymatic catalysis using the effective fragment molecular orbital method: towards all ab initio biochemistry

Area of Science:

• Computational Chemistry
• Quantum Chemistry
• Biomolecular Simulation

Background:

• The Effective Fragment Molecular Orbital (EFMO) method is a quantum mechanical approach for calculating the electronic structure of large molecular systems.
• Simulating complex biochemical reactions requires accurate treatment of electronic polarization effects and efficient computational methods.
• Understanding enzyme mechanisms, such as that of chorismate mutase, is crucial for biochemistry and drug discovery.

Purpose of the Study:

• To extend the EFMO method with a frozen domain approach for optimizing active site geometries while including system-wide polarization effects.
• To efficiently map the entire reaction path of the enzyme chorismate mutase using ab initio calculations.
• To determine the reaction barrier of chorismate mutase with high accuracy.

Main Methods:

• Implementation of the frozen domain approach within the EFMO method.
• Ab initio calculations on a system of 2398 atoms without employing force fields.
• Automatic construction of the reaction path by defining a reaction coordinate.
• Application of the ONIOM (Our Own N-layered Integrated molecular Orbital and molecular Mechanics) method with EFMO-RHF/6-31G(d) for high and low layers.

Main Results:

• The new EFMO frozen domain approach successfully mapped the complete reaction path of chorismate mutase.
• The entire reaction pathway was computed in under four days using 80 cores on 20 nodes.
• The reaction barrier for chorismate mutase was determined to be [Formula: see text] kcal mol(-1) at the MP2/cc-pVDZ level and [Formula: see text] at the MP2/cc-pVTZ level.

Conclusions:

• The frozen domain EFMO method provides an efficient and accurate way to study large molecular systems and enzymatic reactions.
• This approach enables ab initio treatment of complex systems, overcoming limitations of traditional methods.
• The determined reaction barriers offer valuable insights into the catalytic mechanism of chorismate mutase.