Folding of a DNA hairpin loop structure in explicit solvent using replica-exchange molecular dynamics simulations
Srinivasaraghavan Kannan 1 and Martin Zacharias 1*
1 Jacobs University Bremen
* To whom correspondence should be addressed. E-mail: m.zacharias{at}iu-bremen.de.
Submitted on March 2, 2007
Revised on April 18, 2007
Accepted on 22 June 2007
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Abstract |
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Hairpin loop structures are common motifs in folded nucleic acids. The 5'-GCGCAGC sequence in DNA forms a characteristic and stable tri-nucleotide hairpin loop flanked by a two base-pair stem helix. To better understand the structure formation of this hairpin loop motif in atomic detail we employed replica-exchange molecular dynamics (RexMD) simulations starting from a single-stranded DNA conformation. In two independent 36 ns RexMD simulations conformations in very close agreement with the experimental hairpin structure were sampled as dominant conformations (lowest free energy state) during the final phase of the RexMDs (~35% at the lowest temperature replica). Simultaneous compaction and accumulation of folded structures was observed. Comparison of the GCA tri-nucleotides from early stages of the simulations with the folded topology indicated a variety of central loop conformations but also arrangements close to experiment that are sampled before the fully folded structure appeared. Most of these intermediates included a stacking of the C2 and G3 bases which was further stabilized by hydrogen bonding to the A5 base and a strongly bound water molecule bridging the C2 and A5 in the DNA minor groove. The simulations suggest a folding mechanism where these intermediates can rapidly proceed towards the fully folded hairpin and emphasizes the importance of loop and stem nucleotide interactions for hairpin folding. In one simulation a loop motif with G3 in syn-conformation (dihedral flip at N-glycosidic bond) accumulated resulting in a mis-folded hairpin. Such conformations may correspond to long-lived trapped states that have been postulated to account for the slower folding kinetics of nucleic acid hairpins than expected for a semi-flexible polymer of same size.
Key Words:
DNA flexibility, DNA loop motif, GCA trinulcleotide hairpin, nucleic acid dynamics, nucleic acid folding, nucleic acid structure
