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High resolution de‐novo folding of hyperstable RNA tetraloops using molecular dynamics simulations
Author(s) -
Chen Alan Austin,
Garcia Angel E
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb146
Subject(s) - molecular dynamics , pseudoknot , chemistry , rna , stacking , force field (fiction) , folding (dsp implementation) , chemical physics , protein tertiary structure , protein secondary structure , hydrogen bond , crystallography , biophysics , molecule , physics , computational chemistry , biology , biochemistry , quantum mechanics , organic chemistry , electrical engineering , gene , engineering
RNA's biochemical versatility arises from its ability to form tertiary structures, which are governed by the intrinsic flexibility of single‐stranded loops, weak stacking interactions, and non‐canonical hydrogen bonding patterns. However, in contrast to the numerous documented successes in protein folding, there has been no successful reports to‐date of Angstrom‐resolution folding of RNA from the unfolded state. This is caused by intrinsic errors in the force‐field parameters themselves, which have not been significantly improved in 20 years. We present preliminary results of an improved RNA force‐field which has been extensively calibrated against vapor‐pressure osmometry, ultrasonic absorption, NMR, and circular dichroism experiments on short oligonucleotides. Using replica‐exchange molecular dynamics, we are able to reversibly fold all three hyperstable tetraloop motifs (UUCG, GCAA, and CUUG) from the unfolded state. All of the unique non‐canonical interactions observed in high‐resolution structures are recapitulated by the folding simulations with an all‐atom RMSD of 1 to 3 Å. By accurately capturing the balance between the key driving forces for RNA tertiary folding, we anticipate that large‐scale RNA tertiary folding via molecular dynamics simulations will become feasible in the near future.