Short-Range Imbalances in the AMBER Lennard-Jones Potential for (Deoxy)Ribose···Nucleobase Lone-Pair···π Contacts in Nucleic Acids

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
a 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 nonbonded 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, and 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 short-range region of the interaction. Based
on atom-in-molecule polarizabilities and symmetry-adapted perturbation
theory analysis, we inferred that the DHDF-D3 versus 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.