Membrane Pore Formation Unveiled by ∞RETIS Path Sampling: From Thinning to Flip-Flop.

Area of Science:

• Biophysics
• Computational Chemistry
• Membrane Biology

Background:

• Pore formation in lipid bilayers is crucial for membrane functions like fusion, transport, and signaling.
• The precise mechanisms of pore formation are not fully understood due to limitations in conventional simulation techniques.

Purpose of the Study:

• To investigate the molecular mechanisms of pore formation in dimyristoylphosphatidylcholine (DMPC) lipid bilayers.
• To apply a novel path sampling technique, asynchronous and infinite swap version of Replica Exchange Transition Interface Sampling (∞RETIS), for enhanced simulation accuracy.

Main Methods:

• Utilized the asynchronous and infinite swap version of Replica Exchange Transition Interface Sampling (∞RETIS) for molecular dynamics simulations.
• Employed the CHARMM36m force field to model the DMPC lipid bilayer.
• Developed and used an initiation protocol, 'Inf-init', based on ∞RETIS to generate rare event trajectories from equilibrium simulations.

Main Results:

• Identified a sequence of coupled events in pore formation, starting with membrane thinning.
• Determined that pore nucleation is linked to early-stage thinning.
• Found that pore progression requires polar defects and inter-leaflet lipid proximity.
• Observed that lipid flip-flop exclusively occurs through local membrane thinning.
• Noted that pore closure frequently results in asymmetric lipid distributions.

Conclusions:

• The study elucidates key mechanistic steps in lipid bilayer pore formation.
• ∞RETIS and 'Inf-init' provide powerful tools for simulating rare events in membrane biophysics.
• Understanding pore formation dynamics offers insights into membrane transport and fusion processes.