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

Angelo R Carotenuto; Laura Lunghi; Valentina Piccolo; Mahnoush Babaei; Kaushik Dayal; Nicola Pugno; Massimiliano Zingales; Luca Deseri; Massimiliano Fraldi

doi:10.1016/j.jmps.2020.103974

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

J Mech Phys Solids. 2020 Aug:141:103974. doi: 10.1016/j.jmps.2020.103974. Epub 2020 May 22.

Authors

Angelo R Carotenuto¹, Laura Lunghi², Valentina Piccolo³, Mahnoush Babaei⁴, Kaushik Dayal⁴, Nicola Pugno^{3

5

6}, Massimiliano Zingales⁷, Luca Deseri^{3

4

8

9}, Massimiliano Fraldi¹

Affiliations

¹ Department of Structures for Engineering and Architecture, University of Napoli "Federico II", Italy.
² Smiling International School, formerly at the Department of Life Sciences and Biotech., University of Ferrara, Italy.
³ Department of Civil, Environmental and Mechanical Engineering, University of Trento, Italy.
⁴ Department of Civil and Environmental Engineering, Department of Mechanical Engineering, Carnegie Mellon, USA.
⁵ Laboratory of Bio-inspired, Bionic, Nano, Meta Materials & Mechanics, Department of Civil, Environmental and Mechanical Engineering, University of Trento, Via Mesiano, 77, Trento 38123, Italy.
⁶ Griffith Theory Centenary Lab, School of Engineering and Materials Science, Queen Mary University of London, Mile End Road, London E1 4NS, United Kingdom.
⁷ School of Engineering and Materials Science, Queen Mary University of London, Mile End Road, London E1 4NS UK.
⁸ Department of Mechanical Engineering and Material Sciences, SSoE, University of Pittsburgh USA.
⁹ Department of Nanomedicine, The Houston Methodist Research Institute, USA.

Abstract

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 remodelling and change of lipid ordering of the cell membrane allows to predict 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.

Keywords: Cell membrane; G-protein coupled receptors; GPCR; Ligand-receptor; Lipid rafts; Mechanobiology; SARS-CoV-2; Structured deformations.