Large-Scale Density Functional Theory Transition State Searching in Enzymes

Area of Science:

• Biochemistry
• Computational Chemistry
• Enzymology

Background:

• Chorismate mutase catalyzes a key reaction in aromatic amino acid biosynthesis.
• Understanding enzyme mechanisms requires accurate computational models.

Purpose of the Study:

• To investigate the catalytic mechanism of Bacillus subtilis chorismate mutase.
• To determine the energetic contribution of the enzyme to the chorismate to prephenate rearrangement.
• To validate the use of linear-scaling density functional theory for large biomolecular systems.

Main Methods:

• Linear-scaling quantum mechanical density functional theory (DFT) calculations.
• Modeling of large-scale enzyme systems (up to 2000 atoms).
• Natural bond orbital (NBO) analysis.

Main Results:

• Calculated activation energy barrier lowered by 10.5 kcal mol(-1) in the enzyme compared to water.
• Obtained an unbiased, near parameter-free description of the transition state.
• Identified key active site residues stabilizing the transition state.

Conclusions:

• Linear-scaling DFT accurately simulates enzyme catalysis.
• Bacillus subtilis chorismate mutase significantly stabilizes the transition state.
• Computational methods can provide insights into enzymatic reaction mechanisms.