Theoretical predictions of DNA hairpin loop conformations: correlations with thermodynamic and spectroscopic data

Abstract

A computational procedure for generating conformations of DNA hairpin loop structures from a broad range of low-energy starting states is described. The starting point of the modeling is the distribution of oligonucleotide chain conformations obtained from Monte Carlo simulations of feasible dinucleotide steps. Structures which meet the spatial criteria for hairpin loop formation are selected from the distributions and subsequently minimized using all-atom molecular mechanics. Both d(CTnG) and d(CAnG) oligomers, where n = 3, 4, or 5, are modeled. These sequences are chosen because of the large number of published NMR and thermodynamic studies on DNA hairpins containing thymine or adenine residues. The minimized three-dimensional hairpin loop structures are compared with one another as well as analyzed in terms of available experimental data. The computational approach provides the first detailed analysis of DNA hairpin loop structure in terms of a multistate conformational model. Investigation of the minimized conformations reveals several interesting structural features. First, hairpin loops of the same sequence adopt several distinctly different conformations, as opposed to minor variants of the same equilibrium structure, that could potentially interconvert in solution. Second, in contrast to double-helical nucleic acids, the hairpin loop models exhibit hydrophobic and hydrophilic surfaces. The different disposition of hydrophobic groups in loops versus duplexes could modulate both protein-nucleic acid interactions and nucleic acid self-associations. Third, perpendicular aromatic interactions of loop residues are observed in many of the computed hairpins. This sort of interaction might be important in the stabilization of non-hydrogen-bonded nucleic acid secondary and tertiary structures. The predicted structural features in the models help, in addition, to account for the unusual thermodynamic properties of DNA hairpin loops. Comparison of the theoretically-generated NOEs in different structures further reveals that very different molecular structures and interactions can, in principle, produce the same NOEs. The multistate description suggested by this observation differs from the conventional interpretation of DNA solution structure in terms of the fluctuations about a single preferred chain conformation. There is not necessarily only one set of closely related structures consistent with the observed data.

Nucleotide Deletion and P Addition in V(D)J Recombination: a Determinant Role of the Coding-End Sequence†

“…A DNA hairpin has therefore to be seen as a dynamic equilibrium adopting the more favorable energy conformation under a given steric stress. Numerous factors are involved in the counterbalance of stabilities of the loop and the stem regions and determine the predominant conformations of the hairpin (5,10). One very relevant factor is the effect of the base sequence of DNA hairpins on hairpin stability and loop folding (2,13,29,36).…”

Characterization of Nucleic Acids by Nanopore Analysis

“…Hairpins are sequences of single-stranded nucleic acids that fold back on themselves to form hydrogen bonds between Watson-Crick base pairs. 23,24 The entropy and enthalpy components of DNA hairpin formation are readily estimated, and the sequence can be designed so that only intramolecular interactions occur. 25 The expectation was that an exten- Characterization of Nucleic Acids by Nanopore Analysis Deamer and Branton sively hydrogen-bonded hairpin structure might enter the vestibule of an R-hemolysin channel but would not be translocated through the pore until all the hydrogen bonds stabilizing the hairpin spontaneously dissociated.…”

The Hairpin Elements of Nucleic Acid Structure: DNA and RNA Folding

“…Indeed, only few theoretical models, based on first principles, have been proposed in the literature Olson 1982, 1987;Haasnoot et al 1986;Garcia et The Hairpin Elements of Nucleic Acid Structure: DNA and RNA Folding 69 al. 1988; Harvey et al 1988;Erie et al 1993). We will therefore refrain from trying to push the data into a certain mold.…”