In silico studies to uncover the effect of CFTR mutants causing cystic fibrosis

Hegedűs Tamás (2018.03.01-2019.08.31)

MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences

Publication: Quantitative comparison of ABC membrane protein type I exporter structures in a standardized way

Abstract: Cystic fibrosis is a fatal inherited monogenic recessive disease affecting several organs in our body (1:3000 prevalence in the Caucasian population). The disease is associated to the absence of functional CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) chloride channel from the apical membrane of epithelial cells. Over 2,000 mutations are known covering all regions of the protein and the most frequent mutation is the deletion of F508 (ΔF508). This position is located in the N-terminal nucleotide binding domain (NBD1) resulting in the misfolding of this segment. We employ molecular dynamics simulations to detect differences between the dynamics of the wild type, ΔF508, and other mutant forms of NBD1. The simulations will be accelerated by GPU technologies that allow more and longer simulations than before, thus a more exhaustive characterization of the NBD1 conformational space. Our results will contribute to both drug development and understanding the effects of mutations at the atomic level.

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