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Albany 2019: 20th Conversation - Abstracts

Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

Tuning the Hydrogen-bonding Interactions of the AMBER RNA Force Field

Molecular dynamics (MD) simulations became a leading tool for investigation of structural dynamics of nucleic acids. Despite recent efforts to improve the empirical potentials (force fields, ffs), RNA ffs have persisting deficiencies, which hamper their utilization in quantitatively accurate simulations. Previous studies have shown that at least two salient problems contribute to difficulties in description of free-energy landscapes of small RNA motifs: (i) excessive stabilization of the unfolded single-stranded RNA ensemble by intramolecular base-phosphate and sugar-phosphate interactions (Kuhrova et al., 2016), and (ii) destabilization of the native folded state by underestimation of stability of base pairing (Sponer et al., 2018). Here, we introduce a general ff term (gHBfix) that can selectively fine-tune non-bonding interaction terms in RNA ffs, in particular the H-bonds. gHBfix potential affects the pair-wise interactions between all possible pairs of the specific atom types, while all other interactions remain intact, i.e., it is not a structure-based model. In order to probe the ability of the gHBfix potential to refine the ff non-bonded terms, we performed an extensive set of folding simulations of RNA tetranucleotides and tetraloops. Based on these data we propose particular gHBfix parameters to modify the AMBER RNA ff. The suggested parametrization significantly improves the agreement between experimental data and the simulation conformational ensembles, although our current ff version still remains far from being flawless. While attempts to tune the RNA ffs by conventional reparametrizations of dihedral potentials or non-bonded terms can lead to major undesired side effects as we demonstrate for some recently published ffs, gHBfix has a clear promising potential to improve the ff performance while avoiding introduction of major new imbalances.

The authors gratefully acknowledge the support by the Ministry of Education, Youth and Sports of the Czech Republic and Czech Science Foundation no. 18-25349S and by the Operational Programme Research, Development and Education – European Regional Development Fund project no. CZ.02.1.01/0.0/0.0/16_019/0000754.

References

    Kuhrova, P.; Best, R. B.; Bottaro, S.; Bussi, G.; Sponer, J.; Otyepka, M.; Banas, P., Computer Folding of RNA Tetraloops: Identification of Key Force Field Deficiencies. J Chem Theory Comput 2016, 12 (9), 4534-4548.

    Sponer, J.; Bussi, G.; Krepl, M.; Banas, P.; Bottaro, S.; Cunha, R. A.; Gil-Ley, A.; Pinamonti, G.; Poblete, S.; Jurecka, P.; Walter, N. G.; Otyepka, M., RNA Structural Dynamics As Captured by Molecular Simulations: A Comprehensive Overview. Chem Rev 2018, 118 (8), 4177-4338.

Petra Kührová1
Vojtěch Mlýnský2
Marie Zgarbová1
Miroslav Krepl1,2
Giovanni Bussi3
Robert B. Best4
Michal Otyepka1
Jiří Šponer1,2
Pavel Banáš 1,2

1Regional Centre of Advanced Technologies and Materials
Department of Physical Chemistry
Faculty of Science
Palacký University
tř. 17 listopadu 12, 771 46
Olomouc, Czech Republic

2Institute of Biophysics of the Czech Academy of Sciences
Královopolská 135
612 65 Brno, Czech Republic 3Scuola Internazionale Superiore di Studi Avanzati
SISSA
via Bonomea 265
34136 Trieste, Italy

4Laboratory of Chemical Physics
NIDDK Diseases
NIH, Bethesda, MD 20892-0520

Ph: (+420) 585 634 756
Fx: (+420) 585 634 761
Email: petra.kuhrova@upol.cz