Capturing the randomness of lipid flip-flopping

Biological membranes are made up of two asymmetric layers of lipids. While lipids can randomly flip-flop from one layer to the other, membrane proteins sort lipids between the two sides. Researchers want to better understand how lipid flip-flopping and protein sorting interact and shape the overall asymmetric distribution.

To aid in this cause, Nathaniel Wesnak and Markus Deserno quantitatively investigated lipid flip-flop.

“We work out some important but probably underappreciated aspects of lipid flip-flop that are going to be really important if we ultimately want to understand the whole game — chief among them lipid packing and interactions, as well as the probabilistic time evolution of this random process,” said Wesnak.

Existing quantitative approaches to describe lipid flip-flop focus on experimental measurements or calculations at the level of the individual lipid. These do not account for the randomness of lipid dynamics or the membrane stresses that arise as a result of lipid interactions, such as packing or non-ideal mixing.

The authors introduced a framework that treats lipid flip-flops as a series of random events and accounts for lipid interactions, directly coupling flip-flop to membrane stresses. They found membrane stress strongly accelerates flip-flop.

“This work allows us to connect macroscopic observables like asymmetry and mechanical forces to the microscopic lipid dynamics within, while predicting the fluctuating behavior around the deterministic description,” Wesnak said.

This versatile model could be extended to study other aspects of membrane biophysics, including the lipid-sorting proteins.

“Understanding how the constantly moving and reorganizing lipids within biological membranes gives rise to asymmetry remains one of the fascinating open questions in the field, and we hope our new theoretical framework proves useful for exploring it,” Wesnak said.

Source: “Stochastic process description of lipid flip-flop,” by Nathaniel Wesnak and Markus Deserno, Journal of Chemical Physics (2026). The article can be accessed at https://doi.org/10.1063/5.0326588 .

This paper is part of the Festschrift in honor of Kurt Kremer Collection, learn more here .