Molecular insights into 14-membered macrolides using the MM-PBSA method

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• Erythromycin A and roxithromycin are crucial macrolide antibiotics targeting the bacterial 50S ribosomal subunit.
• They inhibit protein elongation by obstructing the nascent peptide exit tunnel.
• The precise molecular mechanism of macrolide binding requires further elucidation.

Purpose of the Study:

• To investigate the molecular interactions of erythromycin A and roxithromycin with the bacterial ribosome.
• To elucidate the binding mechanism and quantify binding affinities using computational methods.
• To identify key residues involved in macrolide binding to the ribosome.

Main Methods:

• Molecular dynamics (MD) simulations were performed to model antibiotic-ribosome interactions.
• Binding free energies were calculated using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method.
• Residue-based energy decomposition analysis was employed to identify key interacting residues.

Main Results:

• Calculated binding free energies showed slight overestimation compared to experimental values but provided insights into binding.
• Decomposition analysis identified critical residues in the binding pocket contributing to macrolide affinity.
• Van der Waals interactions were found to be more significant than electrostatic interactions in macrolide binding.

Conclusions:

• The study provides a quantitative understanding of macrolide antibiotic binding mechanisms at the molecular level.
• Identified key interacting residues can guide the design of novel macrolide antibiotics.
• Findings contribute to the development of safer and more effective macrolide antibiotics.