| Summary: | <p>The mechanosensitive K<sub>2P</sub> K<sup>+</sup> channels play important roles in a wide range of physiological processes, including touch, balance, pain, and hearing. The ability of these channels to sense changes in pressure within the cell membrane is essential to these processes. However, the structural and biophysical mechanisms underlying this remain unclear. In this thesis, multiscale molecular dynamics simulation techniques were used to investigate the biophysical and structural mechanisms underlying mechanosensitivity of K<sub>2P</sub> channels. First, how TREK-2 responded to membrane stretch was investigated by simulating TREK-2 embedded in a POPC bilayer subjected to negative pressure (i.e. positive tension). The results show that TREK-2 is intrinsically sensitive to changes in bilayer tension and that the channel switches conformation from the 'Down' state to the 'Up' state in response to membrane stretch. However, although the pressure profile changes symmetrically in both outer and inner leaflets, the structural response of TREK- 2 is highly asymmetric. The changes mainly occurred in the lower half of protein. TREK-2 was therefore next examined under asymmetric tension (i.e. tension only applied in one of two leaflets). Interestingly, TREK-2 only responded to positive tension in the inner leaflet indicating it has the ability to distinguish a variety of force directions within the membrane. Since, the mechanisms underlying mechanosensitivity and intracellular pH sensitivity are thought to be similar, I also examined the role of a critical mutation in the proximal C-terminus of TREK-1 (E306A). This revealed that E306A mimics the protonated state and changes the preferred environment of this residue from water to lipid and consequently assists movement up towards the bilayer. In addition, a new force analysis tool was developed to provide more insight into why some K<sub>2P</sub> channels are mechanosensitive and some are not. Overall, this thesis improves our understanding of the molecular mechanisms underlying the mechanosensitivity of K<sub>2P</sub> channels and ion channels in general.</p>
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