Physical limits to membrane curvature sensing by a single protein

Membrane curvature sensing is essential for a diverse range of biological processes. Recent experiments have revealed that a single nanometer-sized septin protein has different binding rates to membrane-coated glass beads of 1-$\textmu{}\mathrm{m}$ and 3-$\textmu{}\mathrm{m}$ 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. Protein-membrane association rates may depend on the curvature of the bead, but the strength of this dependence is limited by the fluctuations in membrane height and density.