Related Experiment Videos
Multiple ligand-binding modes in bacterial R67 dihydrofolate reductase
Hernán Alonso1, Malcolm B Gillies, Peter L Cummins
1Computational Proteomics Group, John Curtin School of Medical Research, The Australian National University, P.O. Box 334, 2601, Canberra, ACT, Australia.
Journal of Computer-Aided Molecular Design
|August 2, 2005
Summary
R67 dihydrofolate reductase (DHFR) binding modes were explored using computational methods. Multiple ligand configurations are possible within the active site, influencing drug resistance mechanisms.
Area of Science:
- Biochemistry
- Structural Biology
- Computational Chemistry
Background:
- R67 dihydrofolate reductase (DHFR) confers resistance to trimethoprim.
- R67 DHFR is structurally distinct from chromosomal DHFR.
- Its toroidal structure features a central active-site pore.
Purpose of the Study:
- To investigate the binding modes of ligands within the R67 DHFR active site.
- To elucidate the structural basis of trimethoprim resistance conferred by R67 DHFR.
Main Methods:
- Computational modeling using AutoDock and FlexX.
- Molecular dynamics simulations (4 ns).
- Comparative scoring and interaction analysis.
Main Results:
- Multiple binding modes for dihydrofolate (DHF) and NADPH were identified.
- Ligands adopt a stacked endo-conformation at the pore center, stabilized by specific residues (V66, Q67, I68).
- Ligand tails exhibit varied configurations, with key interactions involving K32 and Y69.
Conclusions:
- R67 DHFR accommodates diverse ligand binding orientations.
- Understanding these modes is crucial for comprehending trimethoprim resistance.
- Computational approaches provide valuable insights into enzyme-ligand interactions.