alpha/gamma Transitions in the B-DNA backbone

Abstract

In the crystal structures of protein complexes with B-DNA, alpha and gamma DNA backbone torsion angles often exhibit non-canonical values. It is not known if these alternative backbone conformations are easily accessible in solution and can contribute to the specific recognition of DNA by proteins. We have analysed the coupled transition of the alpha and gamma torsion angles within the central GpC step of a B-DNA dodecamer by computer simulations. Five stable or metastable non-canonical alpha/gamma sub-states are found. The most favourable pathway from the canonical alpha/gamma structure to any unusual form involves a counter-rotation of alpha and gamma, via the trans conformation. However, the corresponding free energy indicates that spontaneous flipping of the torsions is improbable in free B-DNA. This is supported by an analysis of the available high resolution crystallographic structures showing that unusual alpha/gamma states are only encountered in B-DNA complexed to proteins. An analysis of the structural consequences of alpha/gamma transitions shows that the non-canonical backbone geometry influences essentially the roll and twist values and reduces the equilibrium dispersion of structural parameters. Our results support the hypothesis that unusual alpha/gamma backbones arise during protein-DNA complexation, assisting the fine structural adjustments between the two partners and playing a role in the overall complexation free energy.

Simulation of the interactions between Tröger bases and DNA

“…Although t/t region is considered a local minimum, this conformation is usually found in A-DNA and is associated with a low-twist profile, 45,46 in agreement with the distortions previously observed in 3C. Since parm99 force field is known for presenting a low energy barrier between regions g+/t and t/t , 42 this suggests that the chosen force field (AMBER 03) may favor α/γ transitions into t/t region, thus facilitating the distortions required for intercalation binding mode. However, in a previous work we evaluated AMBER 03 torsional profiles and showed that, although γ:t is indeed a local minimum, α:t conformation corresponds to a high energy barrier (30 kJ mol -1 ).…”

“…The combined analysis of α and γ angles, for instance, is specially relevant for the description of low-twist conformations, which are important during DNA recognition by proteins and small molecules. 42 Moreover, the accumulation of non-canonical α/γ conformations may lead to strong distortions in the double helix and thus monitoring these angles becomes an established stability criterion in molecular dynamic simulations. 43,44 Figure 7 shows as scattered points the values of the α and γ angles sampled in 4000 snapshots along simulations, for the base-pairs belonging to the symmetric Tröger binding site.…”

“…The global minimum is defined in the area enclosed by the solid line and local minima are defined in the areas enclosed by dashed lines. 42 According to Várnai et al, 42 these non-canonical α/γ regions are essentially associated to altered values of roll and twist parameters, which describe curvature and winding of DNA, respectively.…”

Watson–Crick Base‐Pairing Properties of Nucleic Acid Analogues with Stereocontrolled α and β Torsion Angles (α,β‐D‐CNAs)

“…Interestingly, it has been shown recently that the most significant energetic contribution, in terms of backbone distortion induced by proteins, is made by the torsion angle a, most often in the form of noncanonical a/g combinations in which a = g + . [29,30] As already mentioned, LNAs stand out as the single nucleic acid modification that contributes to the highest duplex stability ever obtained by natural Watson-Crick hydrogen bonding. To compare the hybridizing properties of a,b-D-CNAs with LNAs, we incorporated one, two, and three dimeric units 1 a into a 12-mer DNA oligonucleotide sequence that has been extensively used by the Imanishi group to investigate the stabilizing effects induced by LNA substitutions.…”

Structure and Dynamics of Hemimethylated GATC Sites

“…The ␥ angle of C8 was trans for trans hemimethylated DNA and spanned the gaucheϪ to trans range for cis hemimethylated DNA. Molecular simulations of a GpC step of a number of DNA crystal structures showed that, in addition to the canonical ␣/␥ angles (gaucheϪ/gaucheϩ), a few metastable sub-states, including ␣/␥:gaucheϩ/gaucheϪ, exist in DNA-protein complexes and free DNA (29). This ␣/␥:gaucheϩ/gaucheϪ sub-state is accompanied by a BI conformation, which is characterized by an ⑀/: trans/gaucheϪ conformation with the (⑀Ϫ) around Ϫ90°.…”