Abstract
The pH-responsive behavior of six triple-helix DNA nanoswitches, differing in the number of protonation centers (two or four) and in the length of the linker (5, 15 or 25 bases), connecting the double-helical region to the single-strand triplex-forming region, was characterized at the atomistic level through Adaptively Biased Molecular Dynamics simulations. The reconstruction of the free energy profiles of triplex-forming oligonucleotide unbinding from the double helix identified a different minimum energy path for the three diprotic nanoswitches, depending on the length of the connecting linker and leading to a different per-base unbinding profile. The same analyses carried out on the tetraprotic switches indicated that, in the presence of four protonation centers, the unbinding process occurs independently of the linker length. The simulation data provide an atomistic explanation for previously published experimental results showing, only in the diprotic switch, a two unit increase in the pKa switching mechanism decreasing the linker length from 25 to 5 bases, endorsing the validity of computational methods for the design and refinement of functional DNA nanodevices.
Highlights
Accepted: 27 April 2021The possibility to synthesize DNA sequences of any length and scale, the specificity of Watson–Crick base pairing and the possibility to introduce chemical modifications has led to the current use of DNA as an efficient nanoscale building material [1,2,3]
Two collective variables (CVs) were used to describe the triplex-forming oligo unbinding from the duplex region: (1) the distance between the center of mass of the C20 atoms of the nucleotides belonging to the duplex and that of the C20 atoms belonging to the triplex-forming region; (2) the number of hydrogen bonds between the triplex-forming region and the nucleotides belonging to the duplex, using the coordination number (CN)
The triplex-forming oligo (TFO) unbinding profile from the double helix was analyzed in terms of its free energy surface (FES) and plotted as a function of the number of hydrogen bonds (HBs) established between the TFO and the DH, and of the distance between their centers of mass, as reported in Figures 2 and 3 for the diprotic and tetraprotic switches, respectively
Summary
The possibility to synthesize DNA sequences of any length and scale, the specificity of Watson–Crick base pairing and the possibility to introduce chemical modifications has led to the current use of DNA as an efficient nanoscale building material [1,2,3]. Modified triple helix-based nanoswitch designed, with the ability to monitor signed, with the ability to monitor the activity of DNA repair enzymes. In this context, context, the the full full understanding understanding of of the the DNA. Furtheron the length oflength the linker connecting the two the domains It more, it been has been demonstrated that the linker-dependent can beby dissihas demonstrated that the linker-dependent modulationmodulation can be dissipated the pated by the of introduction of fourcenters protonation centersstranded in the single stranded triplex-formintroduction four protonation in the single triplex-forming portion [29]. The red and blue colors indicate the forming the double double helix region, while the black indicates the conserved five-base loop, and the green indicates the TFO. The pictures were produced using the UCSF Chimera 1.12 program [30]
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