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Published on: November 10, 2011
Simulation on the structure of pig liver esterase
Daniel Hasenpusch1, Uwe T Bornscheuer, Walter Langel
1Department of Biophysical Chemistry, Institute of Biochemistry, University of Greifswald, Greifswald, Germany.
Journal of Molecular Modeling
|September 24, 2010
Summary
Molecular dynamics simulations reveal that pig liver esterase (PLE) isoenzyme variations stem from flexible helix structures in the substrate entrance channel, not the active site. This impacts substrate specificity and revises catalytic triad residue assignments.
Area of Science:
- Biochemistry
- Structural Biology
- Computational Chemistry
Background:
- Pig liver esterase (PLE) comprises multiple isoenzymes with varying substrate specificities.
- Understanding the structural basis for these differences is crucial for enzyme engineering and drug development.
Purpose of the Study:
- To elucidate the structural determinants of substrate specificity among PLE isoenzymes using computational methods.
- To investigate the role of specific residues and structural motifs in enzyme function.
Main Methods:
- Homology modeling of PLE based on human carboxyl esterase (hCE).
- Extensive molecular dynamics (MD) simulations of wild-type and mutated PLE isoenzymes.
- Analysis of structural stability, residue dynamics (RMSD), and inter-monomer interactions in PLE trimers.
Main Results:
- Stable structures for PLE isoenzymes (PLE1-6, APLE) were achieved after 12-18 ns MD simulations.
- Mutations primarily affect flexible helical regions, altering the substrate entrance channel structure.
- Substrate specificity variations are attributed to the entrance channel conformation, not active site differences.
- A revised assignment for the catalytic triad residue (GLU 452 instead of GLU 336) was proposed based on simulation data and database statistics.
Conclusions:
- The substrate entrance channel's structural flexibility, influenced by mutations, dictates substrate specificity in PLE isoenzymes.
- Computational simulations provide valuable insights into enzyme structure-function relationships and revise key catalytic residue assignments.
