UUCG RNA Tetraloop as a Formidable Force-Field Challenge for MD Simulations

0540054 - BFÚ 2021 RIV US eng J - Článek v odborném periodiku
Mráziková, Klaudia - Mlýnský, Vojtech - Kührová, P. - Pokorná, Pavlína - Kruse, Holger - Krepl, Miroslav - Otyepka, Michal - Banáš, Pavel - Šponer, Jiří
UUCG RNA Tetraloop as a Formidable Force-Field Challenge for MD Simulations.
Journal of Chemical Theory and Computation. Roč. 16, č. 12 (2020), s. 7601-7617. ISSN 1549-9618. E-ISSN 1549-9626
Grant CEP: GA ČR(CZ) GA20-16554S; GA MŠMT EF15_003/0000477
Institucionální podpora: RVO:68081707
Klíčová slova: UUCG RNA Tetraloop * Force-Field * MD Simulations
Obor OECD: Atomic, molecular and chemical physics (physics of atoms and molecules including collision, interaction with radiation, magnetic resonances, Mössbauer effect)
Impakt faktor: 6.006, rok: 2020
Způsob publikování: Omezený přístup
https://pubs.acs.org/doi/10.1021/acs.jctc.0c00801

Explicit solvent atomistic molecular dynamics (MD) simulations represent an established technique to study structural dynamics of RNA molecules and an important complement for diverse experimental methods. However, performance of molecular mechanical (MM) force fields (Ifs) remains far from satisfactory even after decades of development, as apparent from a problematic structural description of some important RNA motifs. Actually, some of the smallest RNA molecules belong to the most challenging systems for MD simulations and, among them, the UUCG tetraloop is saliently difficult. We report a detailed analysis of UUCG MD ' simulations, depicting the sequence of events leading to the loss of 3finish the UUCG native state during MD simulations. The total amount of MD simulation data analyzed in this work is close to 1.3 ms. We identify molecular interactions, backbone conformations, and substates that are involved in the process. Then, we unravel specific ff deficiencies using diverse quantum mechanical/molecular mechanical (QM/MM) and QM calculations. Comparison between the MM and QM methods shows discrepancies in the description of the 5'-flanking phosphate moiety and both signature sugar-base interactions. Our work indicates that poor behavior of the UUCG tetraloop in simulations is a complex issue that cannot be attributed to one dominant and straightforwardly correctable factor. Instead, there is a concerted effect of multiple ff inaccuracies that are coupled and amplifying each other. We attempted to improve the simulation behavior by some carefully tailored interventions, but the results were still far from satisfactory, underlying the difficulties in development of accurate nucleic acid Ifs.
Trvalý link: http://hdl.handle.net/11104/0317722