Heterogeneous biological membranes regulate protein partitioning via fluctuating diffusivity

TL;DR

This study uses simulations to explore how membrane heterogeneity influences protein diffusion and localization, revealing that fluctuating diffusivity and molecular preferences govern protein partitioning in phase-separated membranes.

Contribution

The paper introduces a coupled Langevin dynamics and phase-field simulation approach to analyze protein diffusion in heterogeneous membranes, highlighting the role of fluctuating diffusivity in protein partitioning.

Findings

Protein diffusivity fluctuates temporally depending on membrane composition.

Molecular crowding and confinement induce subdiffusive behavior.

Protein partitioning is governed by diffusivity differences, molecular preference, and concentration.

Abstract

Cell membranes phase separate into ordered ${\rm L_o}$ and disordered ${\rm L_d}$ domains depending on their compositions. This membrane compartmentalization is heterogeneous and regulates the localization of specific proteins related to cell signaling and trafficking. However, it is unclear how the heterogeneity of the membranes affects the diffusion and localization of proteins in ${\rm L_o}$ and ${\rm L_d}$ domains. Here, using Langevin dynamics simulations coupled with the phase-field (LDPF) method, we investigate several tens of milliseconds-scale diffusion and localization of proteins in heterogeneous biological membrane models showing phase separation into ${\rm L_o}$ and ${\rm L_d}$ domains. The diffusivity of proteins exhibits temporal fluctuations depending on the field composition. Increases in molecular concentrations and domain preference of the molecule induce subdiffusive behavior due to molecular collisions by crowding and confinement effects, respectively. Moreover, we quantitatively demonstrate that the protein partitioning into the ${\rm L_o}$ domain is determined by the difference in molecular diffusivity between domains, molecular preference of domain, and molecular concentration. These results pave the way for understanding how biological reactions caused by molecular partitioning may be controlled in heterogeneous media. Moreover, the methodology proposed here is applicable not only to biological membrane systems but also to the study of diffusion and localization phenomena of molecules in various heterogeneous systems.