Molecular dynamics simulations of heterogeneous cell membranes in response to uniaxial membrane stretches at high loading rates

Lili Zhang,Zesheng Zhang,John Jasa,Dongli Li,Mehrdad Negahban,Antoine Jérusalem,Robin O Cleveland

doi:10.1038/s41598-017-06827-3

Lili Zhang, Zesheng Zhang + Show 5 more

Open Access

https://doi.org/10.1038/s41598-017-06827-3

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Abstract

The chemobiomechanical signatures of diseased cells are often distinctively different from that of healthy cells. This mainly arises from cellular structural/compositional alterations induced by disease development or therapeutic molecules. Therapeutic shock waves have the potential to mechanically destroy diseased cells and/or increase cell membrane permeability for drug delivery. However, the biomolecular mechanisms by which shock waves interact with diseased and healthy cellular components remain largely unknown. By integrating atomistic simulations with a novel multiscale numerical framework, this work provides new biomolecular mechanistic perspectives through which many mechanosensitive cellular processes could be quantitatively characterised. Here we examine the biomechanical responses of the chosen representative membrane complexes under rapid mechanical loadings pertinent to therapeutic shock wave conditions. We find that their rupture characteristics do not exhibit significant sensitivity to the applied strain rates. Furthermore, we show that the embedded rigid inclusions markedly facilitate stretch-induced membrane disruptions while mechanically stiffening the associated complexes under the applied membrane stretches. Our results suggest that the presence of rigid molecules in cellular membranes could serve as “mechanical catalysts” to promote the mechanical destructions of the associated complexes, which, in concert with other biochemical/medical considerations, should provide beneficial information for future biomechanical-mediated therapeutics.

Highlights

Alterations to cellular structures in many human diseases can significantly affect the chemobiomechanical properties of the cell[1]
No significant dependence of rupture processes on the probed strain rates is observed until membrane complexes become severely fragmented. These results indicate that the embedding of rigid molecules in the lipid bilayer membranes could serve as “mechanical catalysts” to enhance the cellular membrane disruptions induced by the applied rapid mechanical stimuli, which, in concert with other biochemical/medical approaches, potentially offers a new efficacious means to rupture diseased cells and/or potentiate sonoporation for local delivery of therapeutic macromolecules
Atomic-level biomolecular simulations have been an active field of research for decades, and, with the continuing improvements in computer hardware, software, and simulation methodologies, have emerged as a powerful tool for the study of biomolecular dynamics at spatiotemporal scales that are difficult to access experimentally[54]

Summary

Introduction

Alterations to cellular structures in many human diseases can significantly affect the chemobiomechanical properties of the cell[1]. It is of substantial relevance to study how changes in molecular structures, cellular biomechanical properties, and biological functions influence, and are influenced by their intricate chemobiomechanical microenvironments and external stimuli, such as shock waves. This understanding could offer valuable insights into new biomechanical-mediated treatment design, and potentially the pathologic basis of disease and disease progression. It has received considerable research attention, a direct quantitative link between molecular-level biological events, such as membrane lipids dissociation, and continuum-level biomechanical concepts, such as membrane mechanoporation, is still largely lacking

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