Paraschiv, Alexandru; (2021) Influence of mechanical forces on the self-organisation of biomolecular systems. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Mechanical forces play a crucial role in shaping the development of tissues and organisms. Nature has evolved intricate ways of utilising mechanical cues in order to achieve various objectives. In this dissertation, we examine the role played by mechanical forces in regulating the function of biological systems at the level of many molecules. We employ computational simulations, using minimal coarse-grained models. This allows us to capture the essential information about the investigated systems as well as to derive general phenomenological insights. We begin with the study of mechanosensitive protein channels, which are a class of transmembrane proteins responsible for sensing the osmotic pressure on cells and protecting them against lysis. Recent experiments suggest that such channels separate into liquid-like clusters, but the functional role of this aggregation is still unknown. We examine the collective behaviour of such proteins and we reveal that a dynamic self-assembly of channels, driven by changes in membrane tension, can control the osmotic pressure equilibration and the volume of the whole cell. We then focus on the growth of membrane protrusions, or tubes, which are thin elongated structures used by cells to sense mechanical stimuli. We investigate the influence of proteins linking the membrane to cytoskeletal components on pulling membrane tubes. We find that the force required to extrude a tube has an intriguing non-linear dependence on the concentration of cortex attachments. Subsequently, we turn our attention to the study of the mechanically-induced self-assembly of fibronectin, a structural protein constituent of the extracellular matrix. We examine the emergent fibrillar architectures and show how the morphologies of these networks change depending on various mechanical parameters. Finally, we explore how a nanoparticle adsorbed on a deformable elastic membrane senses the substrate’s mechanical properties through gradients in the membrane’s bending rigidity. We hope that the results presented in this dissertation will spur further discussions and experimental studies related to the functional role played by mechanical forces in regulating the collective macromolecular behaviour at the nanoscale.

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