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Synchronized conformational fluctuations and binding site desolvation during molecular recognition
Sutjano Jusuf1, Paul H Axelsen
1Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Biochemistry
|December 8, 2004
Summary
Specific structural fluctuations in vancomycin, like peptide group rotations, actively prepare the binding site for ligand entry by synchronizing water expulsion and ring distortion. This reveals a complex preorganization mechanism in molecular recognition.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Binding site desolvation is critical for ligand binding but poorly understood.
- The role and mechanism of structural fluctuations in promoting desolvation remain unclear.
Purpose of the Study:
- To investigate how specific structural fluctuations contribute to ligand binding site desolvation in glycopeptide antibiotics.
- To examine the role of backbone peptide group rotations in vancomycin.
Main Methods:
- Employed a two-dimensional adaptive umbrella sampling molecular dynamics simulation technique.
- Analyzed backbone peptide group rotations in vancomycin.
Main Results:
- Identified small energetic barriers for rotations in key peptide groups of vancomycin.
- Observed that these rotations synchronize water expulsion from hydrogen bond donors and distort the macrocyclic rings.
- Demonstrated that these distortions force water into and out of the binding site, preparing it for ligand recognition.
Conclusions:
- Structural fluctuations, specifically peptide group rotations, are mechanistically linked to binding kinetics and ligand recognition in glycopeptide antibiotics.
- Revealed a high degree of preorganization, complexity, and synchronization in specific molecular recognition.
- Suggested that covalent dimerization strategies to enhance antibiotic affinity may be counterproductive.