title: Structure and Dynamics of DNA and RNA Double Helices Obtained from the GGGGCC and CCCCGG Hexanucleotide Repeats That Are the Hallmark of C9FTD/ALS Diseases.
abstract: A (GGGGCC) hexanucleotide repeat (HR) expansion in the C9ORF72 gene, and its associated antisense (CCCCGG) expansion, are considered the major cause behind frontotemporal dementia and amyotrophic lateral sclerosis. We have performed molecular dynamics simulations to characterize the conformation and dynamics of the 12 duplexes that result from the three different reading frames in sense and antisense HRs for both DNA and RNA. These duplexes display atypical structures relevant not only for a molecular level understanding of these diseases but also for enlarging the repertoire of nucleic-acid structural motifs. G-rich helices share common features. The inner G-G mismatches stay inside the helix in Gsyn-Ganticonformations and form two hydrogen bonds (HBs) between the Watson-Crick edge of Gantiand the Hoogsteen edge of Gsyn. In addition, Gsynin RNA forms a base-phosphate HB. Inner G-G mismatches cause local unwinding of the helix. G-rich double helices are more stable than C-rich helices due to better stacking and HBs of G-G mismatches. C-rich helix conformations vary wildly. C mismatches flip out of the helix in DNA but not in RNA. Least (most) stable C-rich RNA and DNA helices have single (double) mismatches separated by two (four) Watson-Crick basepairs. The most stable DNA structure displays an "e-motif" where mismatched bases flip toward the minor groove and point in the 5' direction. There are two RNA conformations, where the orientation and HB pattern of the mismatches is coupled to bending of the helix.
authors.affiliation: Department of Physics and ‡Center for High Performance Simulations (CHiPS), North Carolina State University , Raleigh, North Carolina 27695-8202, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Physics and ‡Center for High Performance Simulations (CHiPS), North Carolina State University , Raleigh, North Carolina 27695-8202, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Roland
authors.affiliation: Department of Physics and ‡Center for High Performance Simulations (CHiPS), North Carolina State University , Raleigh, North Carolina 27695-8202, United States.
authors.forename: Celeste
authors.identifier: 0000-0002-2750-5186
authors.initials: C
authors.lastname: Sagui
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D020137:Base Pair Mismatch; D000073885:C9orf72 Protein; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D004247:DNA / Q000737:chemistry; D042622:DNA Repeat Expansion; D057180:Frontotemporal Dementia / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D025341:Principal Component Analysis; D011506:Proteins / Q000235:genetics*; D012313:RNA / Q000737:chemistry; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins; D012313:RNA; D004247:DNA
keywords: ALS; C-C and G-G mismatches; C9FTD; Nucleotide repeat disorder; e-motif; hexanucleotide repeat