Membrane Pore Formation Unveiled by ∞RETIS Path Sampling: From Thinning to Flip-Flop
Daniel Tianhou Zhang, Lukas Baldauf, Grzegorz Lazarski, Titus S. van Erp, Wataru Shinoda
TL;DR
This paper uses a new simulation method to reveal how pores form in cell membranes, showing that thinning and lipid flip-flop are key steps.
Contribution
The paper introduces ∞RETIS path sampling to study pore formation, revealing new mechanistic insights previously unattainable with conventional methods.
Findings
Pore nucleation is driven by early-stage membrane thinning.
Lipid flip-flop occurs exclusively via local membrane thinning.
Pore closure often leads to asymmetric lipid distributions.
Abstract
Pore formation in lipid bilayers plays a vital role in membrane fusion, transport, and signaling. Yet, its detailed mechanism remains elusive due to the limitations of conventional simulation methods. To overcome this, we apply a newly developed path sampling technique, the asynchronous and infinite swap version of Replica Exchange Transition Interface Sampling (∞RETIS), to study pore formation in a dimyristoylphosphatidylcholine (DMPC) bilayer modeled with the CHARMM36m force field. Our results reveal a sequence of tightly coupled events: pore nucleation sites are determined by early-stage thinning, and the progress into a metastable pore requires a combination of polar defects and close proximity between lipids across opposite leaflets. Using Inf-init, an initiation protocol based on ∞RETIS, rare trajectories can be generated starting directly from equilibrium simulations. Inf-init…
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Taxonomy
TopicsLipid Membrane Structure and Behavior · Cellular transport and secretion · Nanopore and Nanochannel Transport Studies