Poster abstracts

Poster number 30 submitted by Sanket Walujkar

Ion Permeation in Molecular Dynamics Simulations of TMEM16-based TMC1 Homology Models

Sanket Walujkar (Chemical Physics Graduate Program), Lahiru N Wimalasena, Jeffrey M Lotthammer, Collin Nisler (Biophysics Graduate Program), Jeffrey M Lotthammer, Joseph C Sudar

Abstract:
Mechanical stimuli from sound and head movements are converted into electrical signals in the inner ear during a process known as mechanotransduction. Vibrations in the inner ear fluid - endolymph result in deflections of the hair cell stereocilia. These deflections cause opening of the cation channels at the top of the stereocilia producing an electric signal that is sent to the brain. The molecular identity of the cation channel involved in inner-ear mechanotransduction has been unclear for years, although four transmembrane proteins (PCDH15, TMIE, TMHS, and TMC1) have been shown to be part of the mechanotransduction complex. Recent studies suggest that TMC1 is the pore-forming subunit of the mechanotransduction complex and that it assembles as a dimer (Pan et al, Neuron 2018), yet the structure of TMC1 and the mechanisms of ion conduction and activation remain to be elucidated. Bioinformatic analyses suggest that TMC1 is related to the dimeric TMEM16 family of membrane proteins that includes anion channels and lipid scramblases for which high-resolution structures have been recently reported. Hence, we constructed TMC1 homology models based on the mouse Ca2+-activated chloride channel TMEM16A and the fungal Ca2+-activated lipid scramblase TMEM16. Unlike most ion channels, these templates and consequently, the TMC1 homology models, do not show a central ion conduction pore. Instead, each subunit consists of a hydrated lipid facing groove that forms the ion conduction pathway. Here we present molecular dynamics simulations of these homology models in the presence and the absence of electric field showing ion conduction in agreement with electrophysiological studies.

References:
1. Pan, Bifeng, et al. "TMC1 forms the pore of mechanosensory transduction channels in vertebrate inner ear hair cells." Neuron 99.4 (2018): 736-753.

Keywords: Molecular Dynamics, Ion Channel, Mechanosensation