Molecular Modeling and Simulation of a Synthetic Peptide Channel

Abstract

Many human diseases, including episodic ataxia, diabetes, epilepsy, cystic fibrosis and Alzheimer's dementia, are related to defective ion channels. A series of channel forming peptides derived from the second transmembran domain of the α1-subunit of the glycine receptor (M2GlyR) have been designed by the Tomich lab with improved anion conduction rate and aqueous solubility. To rationally understand the physiological properties of these synthetic channels and to identify improved designs, we combine NMR, biophysical data, and molecular modeling to provide a structural basis for understanding key physiochemical properties that govern the chloride conductivity and selectivity. Initial structural models were first constructed for one of our lead design, p22-T19R/S22W (KKKKP ARVGL GITTV LTMRT QW), primarily based on the monomer structure from solution NMR, amphipathicity consideration, and the oligomeric state of the channel assembly. Long molecular dynamic simulations in explicit membrane and water were then carried out to characterize the channel structural and dynamic properties. Interestingly, independent simulations from initial constructs with different handiness of helix packing (left, straight, and right) all converge to a similar structural ensemble with left-handed helix assembly. The predicted pore-lining residues are also in excellent agreement with a previous set of cysteine-scanning experiments. Coupled with parallel experimental characterizations in the Tomich lab, the simulation provides important insights into the structural basis of the activity of these synthetic channels.