Friedreich’s ataxia, the most common inherited ataxia, is a neurodegenerative disease most commonly caused by an expansion mutation in the first intron of the gene for frataxin. These mutations lead to reduced levels of frataxin which is essential for iron-sulfur cluster (ISC) formation in the larger SDAU(F) complex. In order to find potential small molecule replacements for frataxin, frataxin’s role in ISC synthesis must first be understood. The reaction mechanism is a simple cysteine transfer loop; however, the movement has not been observed in equilibrium simulations. To model this rare event without bias, the WESTPA package was used to run a number of weighted ensemble simulations of the protein complex with and without frataxin. The data generated from these simulations have generated potential of mean force profiles along different reaction coordinates and shows how frataxin affects them, as well as the identification of different metastable states.

Determining the molecular basis for Friedreich’s ataxia using weighted ensemble molecular dynamics simulations

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