A case study comparing quantitative stability-flexibility relationships across five metallo-β-lactamases highlighting...

Area of Science:

• Biophysics
• Structural Biology
• Computational Biology

Background:

• Protein structure-function relationships are key to understanding biological processes.
• Metallo-β-lactamases (MBLs) are clinically significant enzymes conferring antibiotic resistance.
• Quantified Stability-Flexibility Relationships (QSFR) provide insights into protein dynamics.

Purpose of the Study:

• To investigate conserved and varied QSFR across protein families using MBLs as a model.
• To identify specific structural differences in the NDM-1 enzyme.
• To explore the implications of altered flexibility on protein function and drug resistance.

Main Methods:

• Utilizing the Distance Constraint Model (DCM), an ensemble-based biophysical approach.
• Integrating thermodynamic and mechanical perspectives for protein structure analysis.
• Characterizing backbone flexibility and intramolecular couplings in five MBLs.

Main Results:

• Overall backbone flexibility is conserved across the studied MBLs.
• NDM-1 exhibits increased rigidity in specific regions compared to other MBLs.
• NDM-1 displays atypical intramolecular couplings, with limited correlated flexibility isolated to active site loops.

Conclusions:

• QSFR analysis reveals both conserved and distinct dynamic properties across protein families.
• NDM-1's unique structural rigidity and limited correlated flexibility may contribute to its high activity and spread.
• Understanding these dynamic differences is crucial for developing strategies against antibiotic resistance.