Short-range imbalances in the AMBER Lennard-Jones potential for (deoxy)ribose···nucleobase lone-pair···π contacts in nucleic acids - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Journal of Chemical Information and Modeling Année : 2021

Short-range imbalances in the AMBER Lennard-Jones potential for (deoxy)ribose···nucleobase lone-pair···π contacts in nucleic acids

Klaudia Mráziková
Jiří Šponer
Vojtěch Mlýnský
Holger Kruse
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Résumé

The lone-pair…π (lp…π) (deoxy)ribose…nucleobase stacking is a recurring interaction in Z-DNA and RNAs that is characterized by sub-van der Waals lp…π contacts (<3.0 Å). It is part of the structural signature of CpG Z-step motifs in Z-DNA and r(UNCG) tetraloops that are known to behave poorly in molecular dynamics (MD) simulations. Although the exact origin of the MD simulation issues remains unclear, a significant part of the problem might be due to an imbalanced description of non-bonded interactions including the characteristic lp…π stacking. To gain insights into the links between lp…π stacking and MD, we present an in-depth comparison between accurate large-basis-set double-hybrid Kohn-Sham density functional theory calculations DSD-BLYP-D3/ma-def2-QZVPP (DHDF-D3) and data obtained with the nonbonded potential of the AMBER force field (AFF) for NpN Z-steps (N = G, A, C, U). Among other differences, we found that the AFF overestimates the DHDF-D3 lp…π distances by ~0.1-0.2 Å while the deviation between the DHDF-D3 and AFF descriptions sharply increases in the shortrange region of the interaction. Based on atom-in-molecule (AIM) polarizabilities and SAPT analysis, we inferred that the DHDF-D3 vs. AFF differences partly originate in identical nucleobase carbon atom Lennard-Jones (LJ) parameters despite the presence/absence of connected electron withdrawing groups that lead to different effective volumes or vdW radii. Thus, to precisely model the very short CpG lp…π contact distances, we recommend revision of the nucleobase atom LJ parameters. Additionally, we suggest that the large discrepancy between DHDF-D3 and AFF short-range repulsive part of the interaction energy potential may significantly contribute to the poor performances of MD simulations of nucleic acid systems containing Z-steps. Understanding where, and if possible why, the point-charge-type effective potentials reach their limits is vital for developing next-generation FFs and for addressing specific issues in contemporary MD simulations.
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Dates et versions

hal-03420653 , version 1 (24-01-2023)

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Klaudia Mráziková, Jiří Šponer, Vojtěch Mlýnský, Pascal Auffinger, Holger Kruse. Short-range imbalances in the AMBER Lennard-Jones potential for (deoxy)ribose···nucleobase lone-pair···π contacts in nucleic acids. Journal of Chemical Information and Modeling, 2021, ⟨10.1021/acs.jcim.1c01047⟩. ⟨hal-03420653⟩

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