Parametrization of macrolide antibiotics using the force field toolkit

Area of Science:

• Computational chemistry
• Molecular dynamics
• Drug discovery

Background:

• Macrolide antibiotics are crucial for targeting bacterial ribosomes.
• Existing computational models for macrolides are limited due to a lack of specific force field parameters.
• Parametrizing large molecules like macrolides presents unique computational challenges.

Purpose of the Study:

• To develop CHARMM-compatible force field parameters for erythromycin, azithromycin, and telithromycin.
• To establish novel approaches for parametrizing large, complex molecules.
• To evaluate the performance of the developed parameters in molecular dynamics simulations.

Main Methods:

• Utilized the force field toolkit (ffTK) plugin in VMD to determine parameters.
• Investigated two methods for partial atomic charge calculation: interaction with TIP3P water and electrostatic potential.
• Tested multiple approaches for fitting dihedral parameters.
• Performed molecular dynamics simulations of macrolides within the bacterial ribosome.

Main Results:

• Successfully generated CHARMM-compatible force field parameters for key macrolide antibiotics.
• Identified improved methods for parametrizing large molecules using ffTK.
• Molecular dynamics simulations showed enhanced stability and maintenance of critical interactions after parameter refinement.
• Validated the efficacy of the new parameters in accurately modeling macrolide-ribosome interactions.

Conclusions:

• The developed force field parameters significantly improve the accuracy of macrolide simulations.
• Novel parametrization strategies are effective for large molecules.
• This work provides a foundation for future computational studies of macrolide antibiotics and related large molecules.
• Recommended procedures for parametrizing large molecules using ffTK are presented.