Physical limits to membrane curvature sensing by a single protein

TL;DR

This paper investigates the physical limits of membrane curvature sensing by proteins, using continuum models and simulations to explain how proteins like septins can detect micron-scale curvature despite thermal fluctuations.

Contribution

The study develops models and algorithms to quantify physical sensing limits, linking membrane properties and protein size to curvature detection capabilities.

Findings

Experimental sensing efficacy approaches theoretical limits.

Membrane fluctuation variance influences curvature detection sharpness.

Models predict protein-bead association rates based on curvature sensitivity.

Abstract

Membrane curvature sensing is essential for a diverse range of biological processes. Recent experiments have revealed that a single nanometer-sized septin protein can distinguish between membrane-coated glass beads of one micron and three micron diameters, even though the septin is orders of magnitude smaller than the beads. This sensing ability is especially surprising since curvature-sensing proteins must deal with persistent thermal fluctuations of the membrane, leading to discrepancies between the bead's curvature and the local membrane curvature sensed instantaneously by a protein. Using continuum models of fluctuating membranes, we investigate whether it is feasible for a protein acting as a perfect observer of the membrane to sense micron-scale curvature either by measuring local membrane curvature or by using bilayer lipid densities as a proxy. To do this, we develop algorithms to simulate lipid density and membrane shape fluctuations. We derive physical limits to the sensing efficacy of a protein in terms of protein size, membrane thickness, membrane bending modulus, membrane-substrate adhesion strength, and bead size. To explain the experimental protein-bead association rates, we develop two classes of predictive models: i) for proteins that maximally associate to a preferred curvature, and ii) for proteins with enhanced association rates above a threshold curvature. We find that the experimentally observed sensing efficacy is close to the theoretical sensing limits imposed on a septin-sized protein, and that the variance in membrane curvature fluctuations sensed by a protein determines how sharply the association rate depends on the curvature of the bead.