Free Energy of Membrane Pore Formation and Stability from Molecular Dynamics Simulations

Area of Science:

• Membrane biophysics
• Computational biology
• Molecular dynamics simulations

Background:

• Pore formation is vital for biological processes and therapeutic development.
• Experimental methods for studying pore formation lack sufficient temporal and spatial resolution.
• Molecular dynamics (MD) simulations offer a powerful tool to investigate these dynamic processes.

Purpose of the Study:

• To introduce two novel collective variables (CVs) for characterizing membrane pore formation and energetics using MD simulations.
• To provide accurate methods for calculating membrane line tension during pore expansion.
• To assess the performance of different force fields in capturing experimental trends of membrane line tension.

Main Methods:

• Development of two novel collective variables: Full-Path (tracks nucleation and expansion) and Rapid (assesses large pore expansion).
• Utilizing molecular dynamics (MD) simulations to apply these CVs.
• Comparing simulation predictions with experimental data for various lipid compositions and ionic concentrations.

Main Results:

• Both Full-Path and Rapid CVs provide accurate and consistent line tension predictions.
• Predictions qualitatively agree with experimental data, including effects of lipid composition (POPC/POPS, POPC/POPG) and ionic concentration.
• Accurate reproduction of experimental trends is achieved using CHARMM36 and prosECCo75 force fields, while other force fields show varying agreement.

Conclusions:

• The developed CVs offer an efficient and adaptable method for studying pore formation in MD simulations.
• These CVs can be integrated with various simulation engines and applied to systems with external agents.
• The findings highlight the importance of selecting appropriate force fields for accurate simulation of membrane properties.