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Molecular insights into 14-membered macrolides using the MM-PBSA method
Wai Keat Yam1, Habibah A Wahab
1Pharmaceutical Design and Simulation (PhDS) Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Pulau Pinang, Malaysia.
Abstract:
Erythromycin A and roxithromycin are clinically important macrolide antibiotics that selectively act on the bacterial 50S large ribosomal subunit to inhibit bacteria's protein elongation process by blocking the exit tunnel for the nascent peptide away from ribosome. The detailed molecular mechanism of macrolide binding is yet to be elucidated as it is currently known to the most general idea only. In this study, molecular dynamics (MD) simulation was employed to study their interaction at the molecular level, and the binding free energies for both systems were calculated using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. The calculated binding free energies for both systems were slightly overestimated compared to the experimental values, but individual energy terms enabled better understanding in the binding for both systems. Decomposition of results into residue basis was able to show the contribution of each residue at the binding pocket toward the binding affinity of macrolides and hence identified several key interacting residues that were in agreement with previous experimental and computational data. Results also indicated the contributions from van der Waals are more important and significant than electrostatic contribution in the binding of macrolides to the binding pocket. The findings from this study are expected to contribute to the understanding of a detailed mechanism of action in a quantitative matter and thus assisting in the development of a safer macrolide antibiotic.
Insights
Molecular dynamics simulations reveal key interactions of erythromycin A and roxithromycin with the bacterial ribosome. These findings enhance understanding of macrolide antibiotic mechanisms, aiding in the development of safer drugs.
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.
