Mechanobiology predicts raft formations triggered by ligand-receptor activity across the cell membrane

Clustering of ligand-binding receptors of different types on thickened isles of the cell membrane,

namely lipid rafts, is an experimentally observed phenomenon. Although its influence on cell’s

response is deeply investigated, the role of the coupling between mechanical processes and multiphysics

involving the active receptors and the surrounding lipid membrane during ligand-binding

has not yet been understood. Specifically, the focus of this work is on G-protein-coupled receptors

(GPCRs), the widest group of transmembrane proteins in animals, which regulate specific cell

processes through chemical signalling pathways involving a synergistic balance between the cyclic

Adenosine Monophosphate (cAMP) produced by active GPCRs in the intracellular environment and

its efflux, mediated by the Multidrug Resistance Proteins (MRPs) transporters. This paper develops a

multiphysics approach based on the interplay among energetics, multiscale geometrical changes and

mass balance of species, i.e. active GPCRs and MRPs, including diffusion and kinetics of binding and

unbinding. Because the obtained energy depends upon both the kinematics and the changes of species

densities, balance of mass and of linear momentum are coupled and govern the space-time evolution

of the cell membrane. The mechanobiology involving remodeling and change of lipid ordering of

the cell membrane allows for predicting dynamics of transporters and active receptors –in full agreement

with experimentally observed cAMP levels– and how the latter trigger rafts formation and cluster on

such sites. Within the current scientific debate on Severe Acute Respiratory Syndrome CoronaVirus 2

(SARS-CoV-2) and on the basis of the ascertained fact that lipid rafts often serve as an entry port for

viruses, it is felt that approaches accounting for strong coupling among mechanobiological aspects

could even turn helpful in better understanding membrane-mediated phenomena such as COVID-19

virus-cell interaction.