Sequence Context Dependence of Tandem Guanine:Adenine Mismatch Conformations in RNA: A Continuum Solvent Analysis

• Published in: Biophysical journal 2003-07, Vol.85 (1), p.416-425
• Main Authors: Villescas-Diaz, Gilberto, Zacharias, Martin
• Format: Article
• Language: English
• Subjects: Adenine - chemistry; Base Pair Mismatch; Base Sequence; Binding Sites; Computer Simulation; Energy Transfer; Guanine - chemistry; Ions; Models, Molecular; Molecular biology; Molecular Sequence Data; Nucleic Acid Conformation; Nucleic Acids; Ribonucleic acid; RNA; Sequence Alignment - methods; Sequence Analysis, RNA - methods; Solvents - chemistry; Static Electricity; Tandem Repeat Sequences
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/S0006-3495(03)74486-5

Guanine:adenine (G:A) mismatches and in particular tandem G:A (tG:A) mismatches are frequently observed in biological RNA molecules and can serve as sites for tertiary interaction, metal binding and protein recognition. Depending on the surrounding sequence tG:A mismatches can adopt different basepairing topologies. In the sequence context (5′-) G GAC (tandem G:A in bold) a face-to-face (imino or Watson-Crick-like) pairing is preferred whereas in the C GAG context, G and A adopt a sheared arrangement. Systematic conformational searches with a generalized Born continuum model and molecular dynamics simulations including explicit water molecules and ions have been used to generate face-to-face and sheared tG:A mismatches in both C GAG and G GAC sequence contexts. Conformations from both approaches were evaluated using the same force field and a Poisson-Boltzmann continuum solvent model. Although the substate analysis predicted the sheared arrangement to be energetically preferred in both sequence contexts, a significantly greater preference of the sheared form was found for the C GAG context. In agreement with the experimental observation, the analysis of molecular dynamics trajectories indicated a preference of the sheared form in the case of the C GAG-context and a favorization of the face-to-face form in the case of the G GAC context. The computational studies allowed to identify energetic contributions that stabilize or destabilize the face-to-face and sheared tandem mismatch topologies. The calculated nonpolar solvation and Lennard-Jones packing interaction were found to stabilize the sheared topology independent of the sequence context. Electrostatic contributions are predicted to make the most significant contribution to the sequence context dependence on the structural preference of tG:A mismatches.