Bond Bundle Analysis of Ketosteroid Isomerase

Area of Science:

• Biochemistry
• Computational Chemistry
• Enzymology

Background:

• Enzymatic catalysis is crucial for biochemical reactions.
• Understanding the active site dynamics of enzymes like ketosteroid isomerase (KSI) is key to elucidating catalytic mechanisms.

Purpose of the Study:

• To investigate enzymatic catalysis in the KSI active site using bond bundle analysis.
• To identify unique bonding regions and electron density redistribution in response to electric fields and mutations.
• To correlate these changes with catalytic activity enhancement or inhibition.

Main Methods:

• Bond bundle analysis was applied to five KSI systems.
• Calculations of electron density redistribution and regional properties were performed.
• Systems included those with applied electric fields and amino acid mutations.

Main Results:

• Catalytic enhancement is linked to promoting inter- and intra-molecular electron density redistribution within the KSI-docked substrate.
• Bond properties (volume, energy, electron count) respond independently and disproportionately to different perturbations.
• Correlations between bond wedge properties and reaction barrier energies are additive for predicting bond bundle and atomic basin properties.

Conclusions:

• Catalytic enhancement and inhibition involve different mechanisms, with varying utilization of bond properties depending on the perturbation.
• The findings provide a rigorous framework for connecting local charge density shifts to reaction barrier energy changes in enzymatic catalysis.