Molecular mechanisms of cardiac arrhythmias
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. Our molecular understanding of this channel is limited by the lack of crystal structures and molecular models for the I¬Ks channel. We will here combine computational and experimental approaches to build molecular models of the human I¬Ks channel and determine the molecular basis of arrhythmia-causing mutations in the IKs channel. Our computational approaches primarily include homology modeling, Rosetta modeling, metadynamics, and GROMACS refinement to construct open and closed models of the I¬Ks channel and to track gating transitions between these states. We will guide and refine our computational models using experimentally obtained constraints, such as disulphide cross linking data. We will then use these molecular models to construct models of how arrhythmia-causing IKs channel mutations disrupt channel function. For that work, 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. The completion of these aims will form a framework for exploring molecular details of the IKs 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 IKs 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. Erik Lindahl, DBB/SciLifeLab, will act as external expert advisor.