SNIC SUPR
Modulating cellular excitability via effects on voltage gated channels and GPCRs
Dnr:

SNIC 2019/2-34

Type:

SNIC Large Compute

Principal Investigator:

Lucie Delemotte

Affiliation:

Kungliga Tekniska högskolan

Start Date:

2020-01-01

End Date:

2021-01-01

Primary Classification:

10603: Biophysics

Secondary Classification:

10407: Theoretical Chemistry

Allocation

Abstract

Membranes proteins enable cellular communication with the outside world and as such are crucial for cellular function. A key to their biological function is their ability to be regulated by external factors. The biological phenomena at play are complex, and involve the participation of many molecular details within the protein or in its environment. Atomistic molecular dynamics simulations are well suited to probe the interplay between the system’s components, and allow to generate trajectories of the response of these molecular machines to the environment. KCNQ1, for example, the voltage-gated potassium channel that carries out repolarization of the membrane during the cardiac action potential is regulated by the binding of calmodulin (CaM) to its intracellular domains, leading to Ca2+-dependent regulation of its opening and closing. We propose here to decipher the role of specific residues in the interaction between KCNQ1 and CaM by carrying out simulations of chosen mutants and rationalizing their effect using network analysis. Nav1.4, the voltage-gated sodium channel that is responsible for the depolarization phase of the muscular action potential is the target of several medecines. One potentially interesting molecule is cannabidiol (CBD), one of the non-psychotropic drugs present in cannabis. We propose here to evaluate the binding of CBD to sodium channels and explain its inhibitory effect via MD simulations. Finally, activation of GPCRs such as the 2 adrenergic receptor and of the downstream signaling cascade is regulated by the binding of extracellular ligands. We propose here to use our enhanced sampling simulation method to monitor the response of the system to several ligands with different known effects. Understanding the molecular level effect of these ligands will eventually help design medecines with reduced side effects