G-Quadruplex-forming hexanucleotide repeat expansions d(G4C2)n within the human C9orf72 gene is the root cause for familial amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Recent study has shown that TMPyP4, a potent DNA G-quadruplex binder distorts the toxic RNA G-quadruplex structures of the hexanucleitide repeat and blocks interaction of RNA-Binding Proteins. Although the high-resolution structure of DNA G-quadruplex of the hexanucleotide repeat was recently solved, the RNA G-quadruplex structure and the RNA quadruplex structure in complex with TMPyP4 are not available yet. In this study, we built the homology model of the RNA G-quadruplex from its DNA analog using experimental constraints, and its scaffold was maintained in µs MD simulations. Next, we probed the elusive binding behavior of TMPyP4 to the RNA G-quadruplex of the hexanucleotide repeat. Our results indicate that TMPyP4 binds in two major modes (top binding and bottom stacking). Detailed structural, energetic and dynamic properties for theses binding modes were analyzed. This knowledge is useful to optimize G-quadruplex-specific ligands in the treatment of neurodegenerative diseases like ALS and FTD.

Binding of TMPyP4 to RNA G-quadruplex containing ALS and FTD related G4C2 repeat probed by all-atom molecular dynamics simulations with explicit solvent

255th National Meeting (2018)

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