Conformational analysis of DNA-trinucleotide-hairpin-loop structures usinga continuum solvent model

A number of trinucleotide sequences in DNA can form compact and stable hair pin loops that may have significance for DNA replication and transcription. The conformational analysis of these motifs is important for an understand ing of the function and design of nucleic acid structures. Extensive confor mational searches have been performed on three experimentally known trinucl eotide hairpin loops (AGC, AAA, and GCA) closed by a four-base-pair stem. A n implicit solvation model based on the generalized Born method has been em ployed during energy minimization and conformational search. In addition, e nergy-minimized conformers were evaluated using a finite-difference Poisson -Boltzmann approach. For all three loop sequences, conformations close to e xperiment were found as lowest-energy structures among several thousand alt ernative energy minima. The inclusion of reaction-field contributions was f ound to be important for a realistic conformer ranking. Most generated hair pin loop structures within similar to5 kcal mol(-1) of the lowest-energy st ructure have a similar topology. Structures within similar to 10 kcal mol(- 1) could be classified into about five structural families representing dis tinct arrangements of loop nucleotides. Although a large number of backbone torsion angle combinations were compatible with each structural class, som e specific patterns could be identified. Harmonic mode analysis was used to account for differences in conformational flexibility of low-energy sub-st ates. Class-specific differences in the pattern of atomic fluctuations alon g the sequence were observed; however, inclusion of conformational entropy contributions did not change ranking of structural classes. For an addition al loop sequence (AAG) with no available experimental structure, the approa ch suggests a lowest-energy loop topology overall similar to the other thre e loop sequences but closed by a different non-canonical base-pairing schem e.