Structural modeling of hERG channel-drug interactions using Rosetta

Area of Science:

• Cardiovascular Pharmacology
• Molecular Biology
• Biophysics

Background:

• The human ether-a-go-go-related gene (hERG) channel is crucial for cardiac electrical activity but is also a common drug target.
• hERG channel dysfunction, due to genetic mutations or drug block, can lead to dangerous arrhythmias like long QT syndrome.
• The arrhythmogenic potential of hERG blockers varies, possibly due to differential drug binding to distinct channel states.

Purpose of the Study:

• To investigate the atomistic mechanisms underlying state-dependent drug interactions with the hERG channel.
• To differentiate between safe and harmful hERG-blocking drugs based on their binding affinities.
• To explain how certain drugs can facilitate hERG channel function through interactions with open-state pockets.

Main Methods:

• Utilized Rosetta electron density refinement and homology modeling to construct structural models of open and closed hERG channel states.
• Incorporated cryo-electron microscopy structures of hERG and EAG1 channels for model building.
• Employed molecular docking to simulate interactions between various drug forms (charged/neutral) and hERG channel models.

Main Results:

• Developed structural models for wild-type and mutant hERG channels in open and closed states.
• Docking studies revealed state-dependent drug-channel interactions at an atomistic level.
• Identified specific drug interactions with open-state hydrophobic pockets that correlate with hERG channel facilitation.

Conclusions:

• Drug interactions with discrete hERG channel conformational states are critical for determining arrhythmogenicity.
• Atomistic insights from structural modeling and docking can differentiate safe from harmful hERG blockers.
• Understanding these state-dependent interactions may guide the development of safer cardiac drugs.