Novel eGZ-motif formed by regularly extruded guanine bases in a left-handed Z-DNA helix as a major motif behind CGG trinucleotide repeats

Abstract

The expansion of d(CGG) trinucleotide repeats (TRs) lies behind several important neurodegenerative diseases. Atypical DNA secondary structures have been shown to trigger TR expansion: their characterization is important for a molecular understanding of TR disease. CD spectroscopy experiments in the last decade have unequivocally demonstrated that CGG runs adopt a left-handed Z-DNA conformation, whose features remain uncertain because it entails accommodating GG mismatches. In order to find this missing motif, we have carried out molecular dynamics (MD) simulations to explore all the possible Z-DNA helices that potentially form after the transition from B- to Z-DNA. Such helices combine either CpG or GpC Watson-Crick steps in Z-DNA form with GG-mismatch conformations set as either intrahelical or extrahelical; and participating in BZ or ZZ junctions or in alternately extruded conformations. Characterization of the stability and structural features (especially overall left-handedness, higher-temperature and steered MD simulations) identified two novel Z-DNA helices: the most stable one displays alternately extruded Gs, and is followed by a helix with symmetrically extruded ZZ junctions. The G-extrusion favors a seamless stacking of the Watson-Crick base pairs; extruded Gs favor syn conformations and display hydrogen-bonding and stacking interactions. Such conformations could have the potential to hijack the MMR complex, thus triggering further expansion.

van der Waals Parameter Scanning with Amber Nucleic Acid Force Fields: Revisiting Means to Better Capture the RNA/DNA Structure through MD

“…For that reason, the dsDNA DDD sequence was employed to model the B-DNA structure and dynamics when vdW radii are adjusted. However, not all nucleic acid helices embody B-DNA characteristics and recent efforts in force field development have made strides in modeling noncanonical DNA structures (e.g., quadruplexes, Z-DNA). ,,, In the continuing interest of progressing MD modeling of noncanonical nucleic acid structures, the LJbb modifications were incorporated into a Z-DNA hexamer, d­(CGCGCG) (PDB 1ICK ), to observe the effect of helical stability when the vdW radii are altered. It is worth noting that DDD is an NMR structure while the Z-DNA structure is from X-ray diffraction (0.95 Å).…”

Lone Pair…π Contacts and Structure Signatures of r(UNCG) Tetraloops, Z-Turns, and Z-Steps: A WebFR3D Survey

“…Besides r(UNCG) tetraloops, Z-DNA structures also represent a significant challenge for MD simulations [ 53 , 62 , 63 , 64 , 65 ]. This can be linked to an inappropriate representation of Z I /Z II equilibrium states and has been recently addressed through backbone dihedral angle reparameterizations.…”

Computer Aided Development of Nucleic Acid Applications in Nanotechnologies

“…[120] The OL15 version provides better description of Z-DNA. [122,162,163] There have been recent reports that bsc1 may sample unusual β/γ g+/t states in B-DNA and Holliday junctions, which leads to an inclined position of the sugar ring, disturbance of base pairing, and local minor-groove opening. [133,164] The average population of the bsc1 γ-trans states is ≈4% in internal duplex sequences.…”