Harnessing AlphaFold to reveal hERG channel conformational state secrets

To design safe, selective, and effective new therapies, there must be a deep understanding of the structure and function of the drug target. One of the most difficult problems to solve has been resolution of discrete conformational states of transmembrane ion channel proteins. An example is KV11.1 (hERG), comprising the primary cardiac repolarizing current, IKr. hERG is a notorious drug anti-target against which all promising drugs are screened to determine potential for arrhythmia. Drug interactions with the hERG inactivated state are linked to elevated arrhythmia risk, and drugs may become trapped during channel closure. However, the structural details of multiple conformational states have remained elusive. Here, we guided AlphaFold2 to predict plausible hERG inactivated and closed conformations, obtaining results consistent with multiple available experimental data. Drug docking simulations demonstrated hERG state-specific drug interactions in good agreement with experimental result..., The data were obtained from AlphaFold structural prediction, drug docking with Rosetta GALigandDock, and molecular dynamics simulations in Amber. Subsequently, they were analyzed with Python scripts., , # Harnessing AlphaFold to reveal hERG channel conformational state secrets

[https://doi.org/10.5061/dryad.18931zd5x](https://doi.org/10.5061/dryad.18931zd5x)

## Description of the data and file structure

We modeled the hERG channel structures in various states and validated the predictions through extensive computational simulations and comparisons with experimental data. The data were obtained using AlphaFold2 for structural prediction, Rosetta for structural modeling and drug docking, and molecular dynamics simulations.

## Data structure

#### Molecular Dynamics Simulations/

```
\|- |- i_kk_0mV/ # Inactivated model molecular dynamics simulation with only K+ ions initially in selectivity filter | 0 mV membrane voltage
\|- |- |- i_kk_1000ns.dcd # Trajectory file for 1000 ns simulation
\|- |- |- step5_input.pdb # Entire simulation system structure with only K+ ions initially in selectivity filter
\|- |- |- step5_input.psf # Molecular topology file
\|- |- i_kk_500mV/ # Inactivat...