Abstract
Transient Receptor Potential (TRP) channels are a super family of ion channels that have been implicated in the aetiology of a number of medical conditions. TRP channels conduct cations, and most members of this superfamily are described as being non-selective between cation types. However, a number of channels in the TRPV and TRPM subfamilies exhibit remarkable selectivity for Ca2+ or monovalent ions, respectively. In this thesis, the atomistic mechanisms underpinning selective cation permeation in the TRPV and TRPM subfamilies were investigated using atomistic molecular dynamics simulations.Specifically, it was found that the mechanism of Ca2+-selectivity in the TRPV5 and TRPV6 channels is underpinned by a three site knock-on mechanism between adjacent ion binding sites; each of which possesses greater affinity for Ca2+ binding over Na+.
Moreover, it was established that the mechanism of monovalent-selective permeation mechanism in the TRPM5 channel is based upon a two site knock-on mechanism for monovalent cations. By contrast, one of the two cation binding sites is abolished for Ca2+ within the TRPM5 pore cavity, which explains the channel's impermeability to Ca2+ ions.
Finally, a systematic comparison was conducted between the two main methodologies used to create bio-mimetic, transmembrane voltages in atomistic molecular dynamics simulations on the basis of the TRPV3 channel. These comparisons formed an effort to identify any differences that should be taken into account when designing in silico electrophysiology experiments.
Overall, the research presented in this thesis substantially advances the understanding of the selective permeation mechanisms within two classes of ion channels of significant pharmaceutical interest.
| Date of Award | 2023 |
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| Original language | English |
| Awarding Institution |
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| Sponsors | Medical Research Council |
| Supervisor | Ulrich Zachariae (Supervisor) & Geoffrey Barton (Supervisor) |