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Investigation of Activation Mechanism of Mechanosensitive Nano Ion Channels

Bavi, Omid | 2016

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  1. Type of Document: Ph.D. Dissertation
  2. Language: Farsi
  3. Document No: 49404 (48)
  4. University: Sharif University of Technology
  5. Department: Institute for Nanoscience and Nanotechnology
  6. Advisor(s): Vosoughi, Manochehr; Jamali, Yusef; Naghdabadi, Reza
  7. Abstract:
  8. Mechanosensitive (MS) channels are ubiquitous molecular force sensors that respond to a number of different mechanical stimuli including tensile, compressive and shear stress. One of the main mechanisms to functionally study these channels is the patch clamp technique. Here we use continuum mechanics to probe the question of how curvature, in a standard patch clamp experiment, at different length scales (global and local) affects a model MS channel. Firstly, to increase the accuracy of the Laplace’s equation in tension estimation in a patch membrane and to be able to more precisely describe the transient phenomena happening during patch clamping, we propose a modified Laplace’s equation. In order to quantify the effects of local curvature we introduced a coarse grain representative volume element for the bacterial mechanosensitive ion channel of large conductance (MscL) using continuum elasticity. Herein we showed that change in the local curvature of the lipid bilayer can modulate MscL activity considerably by changing both bilayer thickness and lateral pressure profile. In Addition to local bending, we studied the combined effect of hydrophobic mismatch and local bending on the archetypal mechanosensitive channel MscL. In the case of MscL, we showed inward (cytoplasmic) bending can more effectively gate the channel compared to outward bending. Then we indicate that in response to a specific local curvature, MscL inserted in a bilayer with the same hydrophobic length is more expanded in the constriction pore region compared to when there is a protein-lipid hydrophobic mismatch. Given that gating of mechanosentive (MS) channels is driven by a hierarchical cascade of movements and deformations of transmembrane helices in response to bilayer tension, determining the intrinsic mechanical properties of the individual transmembrane helices is therefore central to understanding the intricacies of the gating mechanism of MS channels. We used a constant-force steered molecular dynamics (SMD) approach to perform unidirectional pulling tests on all the helices of MscL in M. tuberculosis and E. coli homologs. We estimated Young’s moduli of the α-helices of MscL to vary between 0.2 and 12.5 GPa with TM2 helix being the stiffest. We also showed In the absence of water, this helix exhibited a much stiffer response. These data shed light on another physical aspect
    underlying hydrophobic gating of MS channels, in particular MscL
  9. Keywords:
  10. Finite Element Modeling ; Mechanical Properties ; Biomembranes ; Nano Channel ; Mechanical Force ; Mechanosensitive Ion Channel

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