Three-Dimensional Structure of RNA Monomeric G-Quadruplex Containing ALS and FTD Related G4C2 Repeat and Its Binding with TMPyP4 Probed by Homology Modeling based on Experimental Constraints and Molecular Dynamics Simulations

Kelly Mulholland, Holli Joi Sullivan, Joseph Garner, Jun Cai, Brian Chen, Chun Wu

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

The G-quadruplex-forming hexanucleotide repeat expansion (HRE), d(G4C2)n, within the human C9orf72 gene is the root cause for familial amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). A recent study has shown that TMPyP4 has good potential to work as a RNA G-quadruplex binder in treating ALS and FTD. Although the high-resolution structure of the monomeric DNA antiparallel G-quadruplex form of the monomeric hexanucleotide repeat was recently solved, the RNA parallel G-quadruplex structure and its complex with TMPyP4 are not available yet. In this study, we first constructed the homology model for the parallel monomeric RNA G-quadruplex of r(G4C2)3G4 based on experimental constraints and the parallel monomeric G-quadruplex DNA crystal structure. Although the G-tetra core of the homology model was stable observed in 15 μs molecular dynamics (MD) simulations, we observed that the loops adopt additional conformations besides the initial crystal conformation, where TMPyP4 binding was found to reduce the loop fluctuation of the RNA monomeric G-quadruplex. Next, we probed the elusive binding behavior of TMPyP4 to the RNA monomeric G-quadruplex. Encouragingly, the binding modes observed are similar to the modes observed in two experimental complexes of a parallel DNA G-quadruplex with TMPyP4. We also constructed a Markov state model to provide insights into the binding pathways. Together, the findings from our study may assist future development of G-quadruplex-specific ligands in the treatment of neurodegenerative diseases like ALS and FTD.

Original languageEnglish (US)
Pages (from-to)57-75
Number of pages19
JournalACS chemical neuroscience
Volume11
Issue number1
DOIs
StatePublished - Jan 2 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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