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Active site dynamics of acyl-chymotrypsin
S Nakagawa1, H A Yu, M Karplus
1Department of Chemistry, Harvard University, Cambridge, Massachusetts 02138.
Proteins
|June 1, 1993
Summary
Molecular dynamics simulations reveal a trapped water molecule crucial for acyl-chymotrypsin deacylation. This water
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Chemistry
Background:
- Acyl-chymotrypsin is a key enzyme in protein digestion.
- Understanding its catalytic mechanism is vital for drug design.
- Previous studies suggested significant conformational changes during catalysis.
Purpose of the Study:
- To investigate the dynamic motions of key components in acyl-chymotrypsin.
- To elucidate the role of water molecules in the catalytic deacylation step.
- To analyze the flexibility of active site residues during the reaction.
Main Methods:
- Stochastic boundary molecular dynamics simulation.
- Analysis of molecular trajectories and hydrogen bonding networks.
- Comparison of simulation results with X-ray crystallographic data.
Main Results:
- A water molecule was identified as trapped between His-57 and the acyl group, facilitating nucleophilic attack.
- This trapped water forms hydrogen bonds with catalytic residues (His-57, Ser-195).
- Active site residues (His-57, Ser-195, Asp-102) exhibit reduced flexibility due to extensive hydrogen bonding.
Conclusions:
- The findings suggest a mechanism where a pre-positioned water molecule, rather than large His-57 movements, drives deacylation.
- The rigidity of active site residues is attributed to interconnected hydrogen bond networks.
- This study provides atomic-level insights into the acyl-chymotrypsin catalytic mechanism.