Journal
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
Volume 10, Issue 1, Pages 463-480Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ct400837p
Keywords
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Funding
- Grant Agency of the Czech Republic [P208/12/1878]
- Ministry of Education, Youth, and Sports of the Czech Republic: project CEITEC, Central European Institute of Technology [CZ.1.05/1.1.00/02.0068]
- Ministry of Education, Youth, and Sports of the Czech Republic: project RCPTM, Regional Centre of Advanced Technologies and Materials from European Regional Development Fund [CZ.1.05/2.1.00/03.0058]
- Ministry of Education, Youth, and Sports of the Czech Republic: project RCPTM-TEAM from the Operational Program Education for Competitiveness, European Social Fund [CZ.1.07/2.3.00/20.0017]
- South Moravian Centre for International Mobility
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Sugar-phosphate backbone is an electronically complex molecular segment imparting RNA molecules high flexibility and architectonic heterogeneity necessary for their biological functions. The structural variability of RNA molecules is amplified by the presence of the 2'-hydroxyl group, capable of forming multitude of intra- and intermolecular interactions. Bioinformatics studies based on X-ray structure database revealed that RNA backbone samples at least 46 substates known as rotameric families. The present study provides a comprehensive analysis of RNA backbone conformational preferences and 2'-hydroxyl group orientations. First, we create a benchmark database of estimated CCSD(T)/CBS relative energies of all rotameric families and test performance of dispersion-corrected DFT-D3 methods and molecular mechanics in vacuum and in continuum solvent. The performance of the DFT-D3 methods is in general quite satisfactory. The B-LYP-D3 method provides the best trade-off between accuracy and computational demands. B3-LYP-D3 slightly outperforms the new PW6B95-D3 and MPW1B95-D3 and is the second most accurate density functional of the study. The best agreement with CCSD(T)/CBS is provided by DSD-B-LYP-D3 double-hybrid functional, although its large-scale applications may be limited by high computational costs. Molecular mechanics does not reproduce the fine energy differences between the RNA backbone substates. We also demonstrate that the differences in the magnitude of the hyperconjugation effect do not correlate with the energy ranking of the backbone conformations. Further, we investigated the 2'-hydroxyl group orientation preferences. For all families, we conducted a QM and MM hydroxyl group rigid scan in gas phase and solvent. We then carried out set of explicit solvent MD simulations of folded RNAs and analyze 2'-hydroxyl group orientations of different backbone families in MD. The solvent energy profiles determined primarily by the sugar pucker match well with the distribution data derived from the simulations. The QM and MM energy profiles predict the same 2'-hydroxyl group orientation preferences. Finally, we demonstrate that the high energy of unfavorable and rarely sampled 2'-hydroxyl group orientations can be attributed to clashes between occupied orbitals.
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