X-ray crystallography can provide important insights into the structure of RNA enzymes (ribozymes). However, the details of a ribozyme's active site architecture are often altered by the inactivating chemical modifications necessary to inhibit self-cleavage. Molecular dynamics (MD) simulations are able to complement crystallographic data and model the conformation of the ribozyme's active site in its native form. However, the performance of MD simulations is driven by the quality of the force field used. Force fields are primarily parametrized and tested for a description of canonical structures and thus may be less accurate for noncanonical RNA elements, including ribozyme catalytic cores. Here, we show that our recent reparametrization of ε/ζ torsions significantly improves the description of the hairpin ribozyme's scissile phosphate conformational behavior. In addition, we find that an imbalance in the force field description of the nonbonded interactions of the ribose 2'-OH contributes to the conformational behavior observed for the scissile phosphate in the presence of a deprotonated G8(-). On the basis of the new force field, we obtain a reactive conformation for the hairpin ribozyme active site that is consistent with the most recent mechanistic and structural data.

§Institute of Biophysics Academy of Sciences of the Czech Republic Kralovopolska 135 612 65 Brno Czech Republic

†Regional Centre of Advanced Technologies and Materials Department of Physical Chemistry Faculty of Science Palacky University tr 17 listopadu 12 771 46 Olomouc Czech Republic

‡Department of Chemistry Single Molecule Analysis Group University of Michigan 930 North University Avenue Ann Arbor Michigan 48109 1055 United States

∥CEITEC Central European Institute of Technology Masaryk University Campus Bohunice Kamenice 5 625 00 Brno Czech Republic

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