SNIC
SUPR
SNIC SUPR
Molecular mechanisms of cardiac arrhythmias
Dnr:

SNIC 2018/3-316

Type:

SNAC Medium

Principal Investigator:

Sara Liin

Affiliation:

Linköpings universitet

Start Date:

2018-07-01

End Date:

2019-07-01

Primary Classification:

10603: Biophysics

Secondary Classification:

10602: Biochemistry and Molecular Biology

Webpage:

Allocation

Abstract

The cardiac I¬Ks channel, formed by Kv7.1 and KCNE1, is one of the most important repolarizing channels in the heart. More than 300 mutations in the genes encoding Kv7.1 and KCNE1 have been identified in patients with cardiac arrhythmias such as Long-QT syndrome. How specific mutations cause cardiac arrhythmia is however not known for many Kv7.1 and KCNE1 mutations. Moreover, there are presently no clinically approved drugs that target the I¬Ks channel, to be used in the treatment of Long-QT syndrome. However, we have previously shown in experimental studies that analogues of polyunsaturated fatty acids are promising I¬Ks channel modulators (e.g. Liin et al. PNAS 2015; Liin et al. eLife 2016). In this overall project, we combine computational and experimental (site-directed mutagenesis and electrophysiology) approaches to build molecular models of the human I¬Ks channel and determine the molecular basis of arrhythmia-causing mutations in the I¬Ks channel and how analogues of poyunsaturated fatty acids interact with the channel to restore channel function. Our computational approaches primarily include homology modeling, Rosetta modeling, metadynamics, and GROMACS refinement to construct open and closed models of the I¬Ks channel, to track gating transitions between these states, and to probe interactions between fatty acid analogues and the channel. We will guide and refine our computational models using experimentally obtained constraints, such as disulphide cross linking data and mutagenesis data. To construct models of how arrhythmia-causing I¬Ks channel mutations disrupt channel function, experimentally obtained constraints will primarily be combined with in silico mutagenesis and metadynamics to, for instance, estimate how specific mutations affect free energy changes as the channel moves between open and closed conformations. To probe the interaction between fatty acid analogues and the I¬Ks channel, experimentally obtained insights will primarily be combined with molecular dynamics simulations to track interactions between analogues with different properties and the channel. The completion of these aims will form a framework for exploring molecular details of the I¬Ks channel and lead to an understanding of how mutations in Kv7.1 and KCNE1 cause pathophysiological clinical phenotypes. The anticipated results will also provide a molecular framework for our ongoing intelligent design of novel pharmacological compounds that target the I¬Ks channel to restore I¬Ks channel function and thus cardiac function. The computational work will be performed by Liin/Yazdi at Linköping University. Samira Yazdi is a Postdoctoral Fellow in the Liin Lab at Linköping University.