Molecular Biomechanics Controls Protein Mixing and Segregation in Adherent Membranes.

Long Li,Bernd Henning Stumpf,Ana-Sunčana Smith

doi:10.3390/ijms22073699

Abstract

Cells interact with their environment by forming complex structures involving a multitude of proteins within assemblies in the plasma membrane. Despite the omnipresence of these assemblies, a number of questions about the correlations between the organisation of domains and the biomechanical properties of the involved proteins, namely their length, flexibility and affinity, as well as about the coupling to the elastic, fluctuating membrane, remain open. Here we address these issues by developing an effective Kinetic Monte Carlo simulation to model membrane adhesion. We apply this model to a typical experiment in which a cell binds to a functionalized solid supported bilayer and use two ligand-receptor pairs to study these couplings. We find that differences in affinity and length of proteins forming adhesive contacts result in several characteristic features in the calculated phase diagrams. One such feature is mixed states occurring even with proteins with length differences of 10 nm. Another feature are stable nanodomains with segregated proteins appearing on time scales of cell experiments, and for biologically relevant parameters. Furthermore, we show that macroscopic ring-like patterns can spontaneously form as a consequence of emergent protein fluxes. The capacity to form domains is captured by an order parameter that is founded on the virial coefficients for the membrane mediated interactions between bonds, which allow us to collapse all the data. These findings show that taking into account the role of the membrane allows us to recover a number of experimentally observed patterns. This is an important perspective in the context of explicit biological systems, which can now be studied in significant detail.

Highlights

Cell adhesion is a complex biological process involving a variety of receptors and their ligands of different length, flexibility and affinity [1] and is involved in numerous cellular processes [2]
We presented a simulation protocol for studying cell adhesion with a binary mixture of ligands and receptors
The characteristic feature of our approach is an accurate description of membrane mediated correlations between bonds, which were previously shown to be the key for successful modeling of adhesion mediated by a single ligand-receptor pair [11]

Summary

Introduction

Cell adhesion is a complex biological process involving a variety of receptors and their ligands of different length, flexibility and affinity [1] and is involved in numerous cellular processes [2]. More complex transient adhesion domains were found dependent on the diffusive properties of binders [21], while complex structures, including bullseyes pattern characteristic in adherent T-Cells, required the introduction of active forces [20] Despite these efforts, small stable domains, or even domains containing more than one type of bridge have not been reported in mimetic systems so far, commonly appearing in the cellular context. We implicitly account for the effects of the membrane, and are able to study the pattern formation on time scales of microseconds to hours, in a system which has the size of a cell, yet resolving each protein We use this model to test binary mixtures of ligand-receptor pairs to study the steady state organization of bonds as a function of the lengths and intrinsic binding strength of the contributing proteins. On the left part of the frame, the receptors on the mimetic cell are shown with green and black, while on the right half, the ligands on the support are shown with yellow and white dots

Effect of the Difference in the Length of Ligand-Receptor Pairs

Effect of the Intrinsic Binding Affinities

Conclusions

Methods