Membrane Permeability of Sucrose Calculated from Equilibrium Time-Correlation Functions Using Molecular Dynamics...

Area of Science:

• Computational chemistry
• Biophysics
• Molecular dynamics

Background:

• Accurate computation of membrane permeability is crucial for drug discovery and understanding biological processes.
• Traditional methods like equilibrium simulations struggle with molecules exhibiting significant free energy barriers.
• Existing models, such as the inhomogeneous solubility diffusion (ISD) model, rely on assumptions like overdamped dynamics that may not always hold true.

Purpose of the Study:

• To present a novel computational framework for rigorously calculating membrane permeability of small molecules.
• To develop a method that overcomes the limitations of traditional approaches for molecules with high energy barriers.
• To provide a more accurate alternative to the ISD model by accounting for non-Markovian effects.

Main Methods:

• Utilizes committor probability within the transition path theory framework.
• Combines enhanced sampling for potential of mean force with reweighted ensembles of short unbiased trajectories.
• Calculates equilibrium time-correlation functions and steady-state flux from unbiased dynamics.
• Applies the method to sucrose permeation and compares results with the ISD model for DOPC and DLPC membranes using different force fields.

Main Results:

• The developed method provides a rigorous computational route to determine permeability coefficients.
• Committor-based calculations yield permeability estimates that are generally higher than or equal to those from the ISD model.
• The discrepancy suggests that the ISD model potentially ignores non-Markovian memory effects relevant to membrane crossing.

Conclusions:

• The committor probability-based framework offers a robust and accurate method for computing membrane permeability.
• This approach advances beyond the assumptions of the ISD model, particularly for complex permeation processes.
• The findings highlight the importance of considering non-Markovian dynamics in membrane transport simulations.