Exploring polymorphisms in B-DNA helical conformations

Abstract

The traditional mesoscopic paradigm represents DNA as a series of base-pair steps whose energy response to equilibrium perturbations is elastic, with harmonic oscillations (defining local stiffness) around a single equilibrium conformation. In addition, base sequence effects are often analysed as a succession of independent XpY base-pair steps (i.e. a nearest-neighbour (NN) model with only 10 unique cases). Unfortunately, recent massive simulations carried out by the ABC consortium suggest that the real picture of DNA flexibility may be much more complex. The paradigm of DNA flexibility therefore needs to be revisited. In this article, we explore in detail one of the most obvious violations of the elastic NN model of flexibility: the bimodal distributions of some helical parameters. We perform here an in-depth statistical analysis of a very large set of MD trajectories and also of experimental structures, which lead to very solid evidence of bimodality. We then suggest ways to improve mesoscopic models to account for this deviation from the elastic regime.

Multiscale simulation of DNA

“…In any case, at least in our hands, a simple scaling of van der Waals parameters [46] This result argue the prevalent idea that DNA deformation can be described by means of nearneighbor harmonic models [40•]. An in-depth analysis of non-harmonic deformations in DNA [41,58] characterized the atomistic mechanisms of this movement, the role of ions in DNA polymorphism, and the surprising correlation between apparently disconnected degrees of freedom in the DNA.…”

The Role of Unconventional Hydrogen Bonds in Determining BII Propensities in B-DNA

“…In addition, both experimental sources of BII values suffer from a sequence bias due to the limited number of tetranucleotide represented in the limited set of sequence available 20,22,29 .…”

Contributions of Sequence to the Higher-Order Structures of DNA

“…If the distributions of parameters in a large sample of known structures are Gaussian, the mean values will provide a good approximation of the equilibrium rest states and the widths of the distributions will provide an estimate of the elastic constants governing the spatial arrangements of neighboring basepairs. The original estimates of DNA sequence-dependent structural deformability, derived nearly 20 years ago from the few available well-resolved, DNA-containing crystal structures (6), have been supplemented over the years by analyses of larger, better-resolved, nonredundant structural data sets (29) and by massive atomic-level simulations with the capability to examine the influence of sequence content (e.g., nonadjacent nearby residues) on double-helical structure and deformability (30)(31)(32).Until very recently, the predicted effects of sequence on DNA structure failed to account for many key features of the double-helical molecule, including the basepair twist-a parameter that can be reliably measured in solution, gels, and the solid state (33-37). In particular, atomic-level simulations based on some of the most widely used nucleic-acid force fields predicted the twist angle of a generic DNA basepair step (a step generated by averaging the twist angles over all possible combinations of adjacent basepairs) to be~1.2 lower on average than the corresponding values compiled from experiments on mixed-sequence DNA (Fig.…”

“…If the distributions of parameters in a large sample of known structures are Gaussian, the mean values will provide a good approximation of the equilibrium rest states and the widths of the distributions will provide an estimate of the elastic constants governing the spatial arrangements of neighboring basepairs. The original estimates of DNA sequence-dependent structural deformability, derived nearly 20 years ago from the few available well-resolved, DNA-containing crystal structures (6), have been supplemented over the years by analyses of larger, better-resolved, nonredundant structural data sets (29) and by massive atomic-level simulations with the capability to examine the influence of sequence content (e.g., nonadjacent nearby residues) on double-helical structure and deformability (30)(31)(32).…”

“…(A) Average sequence-dependent values of the twist angle between successive basepairs grouped by chemical class (pyrimidine-purine, purine-purine, and purine-pyrimidine). Gold, trends deduced from early biophysical studies of DNA in gels and in solution (35); violet, values accumulated over time in crystal structures of protein-bound DNA (6,29) and a mix of ligand-bound and free DNA (31); green, values predicted with increasingly improved atomic force fields (30)(31)(32). Note that the twist of a generic, sequence-averaged DNA step (MN) found in the most recent data corresponds to a helix with a nucleotide repeat close to the~10.5 bp/turn repeat of mixed-sequence DNA (dashed line) (33,34,36) and that large changes in twist at pyrimidine-purine steps underlie this improvement.…”