Bavi, Navid (2017) Mechanosensitive Ion Channels: From Membrane Mechanics to Channel Structural Dynamics. PhD thesis, Victor Chang Cardiac Research Institute.
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Navid Bavi 2017 PhD thesis UNSW VCCRI.pdf Download (15MB) | Preview |
Abstract
Lipid bilayers of cellular membranes play a key role in modulation of membrane proteins, particularly mechanosensitive (MS) channels. Thus, it is imperative to characterise their mechanical properties. In Chapter 2, a novel conceptual framework is introduced, based on excised patch fluorometry. This framework includes a new hyper-elastic model, which is superior to existing models at describing the overall behaviour of lipid bilayers. Importantly, my computational data illustrates that, contrary to the widely-used Laplace’s equation that manifests in uniform tension across the membrane, tension is heterogeneous throughout the liposome patch. Here, I describe another significant finding, that there is a substantial difference in tension between the outer and inner monolayers of the lipid bilayer in an excised patch configuration that is absent in cell-attached configuration. These results highlight the need for caution against extrapolation of MS channel behaviour from one patch configuration to another.In chapter 3, I explore the MS channel structural dynamics building upon my previous findings from chapter 2. Specifically, a multidisciplinary approach was used involving both experimental and computation methods to study the gating cycle of MscL in response to membrane tension. It has unequivocally been shown that the intracellular amphipathic N-terminal helix of MscL is a crucial mechanosensing element that acts as a linker between membrane dynamics and conformational changes to the channel protein. Such intracellularly located horizontal force-coupling helices may represent an important conserved structural entity that underlies mechanosensitivity of most currently known MS channels.In Chapter 4, I characterize the MscL mechanical properties as a protein scaffold using molecular dynamics (MD) simulation. The Young’s modulus of the alpha-helices of Mycobacterium tuberculosis MscL and E. coli MscL channels was calculated to be between 0.2 and 12.5 GPa. Finally, results from extensive steered MD simulations demonstrate that constant-force method is more reliable than constant-velocity method for measuring Young’s moduli of alpha-helices. Overall, this thesis advances our understanding of the basic physical principles underlying mechanotransduction on both cellular and molecular levels.
| Item Type: | Thesis (PhD ) |
|---|---|
| Additional Information: | SUPERVISORS: Martinac, Boris, Victor Chang Cardiac Research Institute, Faculty of Medicine, UNSW; Hill, Adam, Victor Chang Cardiac Research Institute, Faculty of Medicine, UNSW; Qin, Qinghua, The Australian National University. |
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 08 Aug 2017 21:57 |
| Last Modified: | 10 Sep 2018 05:30 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/615 |
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