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Domain motions in dihydrofolate reductase: a molecular dynamics study
C S Verma1, L S Caves, R E Hubbard
1Department of Chemistry, University of York, Heslington, UK.
Journal of Molecular Biology
|March 7, 1997
Summary
Molecular dynamics simulations reveal two distinct domains in Lactobacillus casei dihydrofolate reductase that move in tandem. This domain motion influences how the enzyme binds both coenzyme NADPH and methotrexate.
Area of Science:
- Biochemistry
- Computational Biology
- Enzymology
Background:
- Dihydrofolate reductase (DHFR) is a crucial enzyme in folate metabolism.
- Understanding DHFR's dynamic behavior is key to drug design.
- Lactobacillus casei DHFR serves as a model system for studying enzyme mechanisms.
Purpose of the Study:
- To investigate the dynamic correlations and domain motions in Lactobacillus casei dihydrofolate reductase.
- To elucidate the relationship between enzyme domain movements and substrate/inhibitor binding.
- To explore the role of water molecules in enzyme dynamics.
Main Methods:
- Molecular dynamics (MD) simulations of DHFR complexed with methotrexate and NADPH.
- Analysis of atomic fluctuation correlations to identify domain movements.
- Quasiharmonic vibrational analysis to determine dominant low-frequency modes.
Main Results:
- Identified two distinct, rotating domains: an
- adenosine-binding domain
- and a
- large domain
- with correlated atomic motions.
- Observed significant correlation between NADPH and methotrexate binding sites, mediated by domain rotation.
- Low-frequency domain motions govern overall enzyme dynamics and couple substrate/inhibitor binding sites.
Conclusions:
- The relative motion of DHFR domains is a critical mechanism for regulating substrate and inhibitor binding.
- Enzyme dynamics, particularly low-frequency domain movements, play a vital role in DHFR's catalytic function.
- MD simulations provide valuable insights into the allosteric regulation of DHFR.