Poster abstracts
Poster number 37 submitted by Collin Nisler
Gating mechanisms of an ancient TRP channel in yeast revealed by molecular dynamics simulations
Collin Nisler (Biophysics), Sanket Walujkar (Chemical Physics), Marcos Sotomayor (Chemistry and Biochemistry)
Abstract:
Transient receptor potential (TRP) channels are a ubiquitous family of membrane proteins found in organisms as distantly related as yeast, insects, and mammals, and perform equally diverse biological functions ranging from mechanosensation to cardiac regulation. In S. cerevisiae, the TRP family member vacuolar transient receptor potential yeast 1 (TRPY1) acts as a defense against hyperosmotic shock by releasing Ca2+ from the vacuolar lumen, restoring equilibrium pressure across the plasma membrane. While experiments have shown TRPY1 can be gated by voltage and mechanical stimuli, and its activity is modulated by the binding of both Ca2+ and the lipid co-factor PI(3)P, the molecular details of these mechanisms remain unknown. Here, all-atom molecular dynamics (MD) simulations were performed on the TRPY1 heterotetramer structure that was recently solved using cryo-electron microscopy at 3.1 Å resolution by our collaborators (T. Ahmed, C. R. Nisler, E. C. Fluck III, M. Sotomayor, V. Y. Moiseenkova-Bell, https://www.biorxiv.org/content/10.1101/2020.10.12.336495v1). Multiple simulations performed in conditions that represented different potential physiological states of TRPY1 revealed the effects that PI(3)P and Ca2+ binding can have on the dynamics, potential conductivity, and allosteric communication pathways of the channel. The results of the MD simulations suggest a molecular explanation for the inhibitory effect of PI(3)P and luminal Ca2+ binding as determined by experiments. Simulations also reveal the local destabilizing effect and disruption of allosteric communication pathways that several gain of function mutations have on key structural features, thus providing an explanation for the increased activity afforded by these mutations. Finally, we obtained a model of the open state of TRPY1 through the application of an expanding force applied to the protein radially from the center of the pore. The conductance of this open state measured in silico agrees well with experimental results. Overall, our MD simulations offer detailed molecular insight into the function and dynamics of this ancient ion channel.
Keywords: TRP Proteins, Ion Channels, Molecular Dynamics