Improved Sampling and Free Energy Estimates for Antibiotic Permeation through Bacterial Porins

Area of Science:

• Computational Chemistry
• Molecular Dynamics
• Drug Discovery

Background:

• Antibiotics utilize bacterial outer membrane protein channels for cellular entry.
• Understanding these transport mechanisms is crucial for developing new antibacterials.
• Accurate free energy calculations are needed to compare antibiotic permeation.

Purpose of the Study:

• To overcome sampling limitations in free energy calculations for antibiotic translocation.
• To compare the efficacy of temperature-accelerated sampling methods.
• To model the transport of bulky solutes, using ciprofloxacin through OmpF as a model system.

Main Methods:

• Employed two sampling methods combining umbrella sampling and metadynamics with temperature acceleration.
• Utilized collective variables for solute degrees of freedom and solute-water interactions.
• Compared well-tempered metadynamics with its temperature-accelerated variant and temperature-accelerated sliced sampling.

Main Results:

• Including collective variables for solute and solvent interactions significantly reduced sampling issues.
• Temperature-accelerated sliced sampling demonstrated superior performance in improving sampling and convergence.
• The ciprofloxacin-OmpF system served as an effective model for bulky solute transport.

Conclusions:

• Temperature-accelerated molecular dynamics approaches enhance the accuracy and efficiency of free energy calculations.
• The temperature-accelerated sliced sampling method offers a robust strategy for studying antibiotic permeation.
• These advancements facilitate the quantitative comparison of antibiotic transport mechanisms.