Allosteric Regulation of Ion Channels

Dnr:

SNIC 2016/1-560

Type:

SNAC Medium

Principal Investigator:

Lucie Delemotte

Affiliation:

Kungliga Tekniska högskolan

Start Date:

2016-12-21

End Date:

2018-01-01

Primary Classification:

10603: Biofysik

Secondary Classification:

10602: Biokemi och molekylärbiologi

Webpage:

https://www.scilifelab.se/researchers/lucie-delemotte/

Allocation

Abstract

Ion channels are membrane proteins that enable communication of the cell with its external environment. Essential for any life form, they enable the selective diffusion of ions, across the otherwise impermeable cellular and organellar envelopes, the lipidic membranes. To enable the controlled opening and closing of these channels, many different families of ion channels exist, that are gated by various stimuli such as changes in heat, pH, electrical signals, binding of chemicals… As other biological systems, many aspects of ion channel function are difficult to study because of the broadness of the time and length scales over which they operate: their gating may be triggered by the binding of a chemical which occurs at the sub-nanometer length-scale, where properties as subtle as a single hydrogen bond may be crucial. The gating may involve several structural elements and thus take place at the nanometer length scale and on the microsecond time scale. However, many regulatory factors operate at a larger, up to the micrometer, scale: the channels may function as macromolecular complexes, or within specific membrane regions. Moreover, the effect of minuscule perturbation, such as the mutation in a single protein amino-acid can propagate to much larger scales and may have effects not only at the cellular level but may also impact the function of entire organs and organisms by causing, for example heart failure or epilepsies. Over the years, many experimental techniques have been developed to study ion channels both structurally and functionally. Great advances have been made, enabling to study channels at the single molecule level. However, the interpretation of experiments is not always straightforward and requires sophisticated modeling strategies. I propose to use molecular dynamics (MD) simulations to study the biophysical properties of the calcium and voltage-activated ion channel AtTPC1 in a truly multi-scale approach. For the first time, a high-resolution structure of a member of this channel family was solved in 2015. Its three-dimensional arrangement ressembles that of the well-known voltage-gated ion channel family. Instead of being a homotetramer like votage-gated potassium channel and bacterial sodium ones, it is made of the dimeric assembly, each monomer containing two homologuous domains: Domain I is regulated by Ca2+ while DII is sensitive to voltage. This enables to tackle the question of the propagation of the two separate stimuli to a single activation gate a by two independent stimuli. The progress made in these last years in computer hardware and software is such that biomolecular problems of this scope can be now tackled. Moreover, many data analysis tools have emerged in the past few years that enable to make sense of the enormous amount of data produced by molecular simulations and infer properties as complicated as the kinetics of the processes.