Calculation of Lipid-Bilayer Permeabilities Using an Average Force.

Area of Science:

• Computational chemistry
• Biophysics
• Pharmacology

Background:

• Assessing drug candidate bioavailability requires accurate lipid bilayer permeability calculations.
• The solubility-diffusion model is limited by difficulties in calculating diffusivity and potential biases.

Purpose of the Study:

• To develop a precise method for calculating free energy and diffusivity for lipid bilayer permeation.
• To identify key factors influencing permeability predictions in molecular simulations.

Main Methods:

• Utilized importance-sampling simulations with adaptive biasing force.
• Employed a Bayesian-inference algorithm for enhanced precision and spatial resolution.
• Conducted multi-microsecond simulations to analyze methodological sensitivities.

Main Results:

• Achieved noteworthy precision and spatial resolution in determining free energy and diffusivity.
• Identified force field parameters and diffusivity time scales as major sources of uncertainty.
• Observed membrane distortion effects impacting permeability estimates.

Conclusions:

• The combined adaptive biasing and Bayesian inference method significantly improves permeability calculations.
• Force field accuracy and appropriate time scale selection are critical for reliable predictions.
• Further advancements in force fields and kinetic models are needed to minimize systematic errors.