UNCG RNA tetraloop as a formidable force-field challenge for MD simulations

Abstract

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 (ffs) 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 UNCG tetraloop is saliently difficult. We report a detailed analysis of UNCG MD simulations, depicting the sequence of events leading to the loss of the UNCG native state during MD simulations. We identify molecular interactions, backbone conformations and substates that are involved in the process. The total amount of MD simulation data analyzed in this work is close to 1.3 millisecond. 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 UNCG 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 are still far from satisfactory, underlying the difficulties in development of accurate nucleic acids ffs.

Conformational Ensembles of Noncoding Elements in the SARS-CoV-2 Genome from Molecular Dynamics Simulations

“…In one of the two simulations we observe the transient formation of a U200–U205 base-pair capped by a canonical UUCG tetraloop fold . The low population of this state is not surprising, as the canonical UUCG tetraloop fold has been shown not to be stabilized to a sufficient degree within this force field . While the detailed architecture of the hexaloop has not yet been solved experimentally, , our computational prediction and available NMR data cannot be easily reconciled in this case.…”

“…51 The low population of this state is not surprising, as the canonical UUCG tetraloop fold has been shown not to be stabilized to a sufficient degree within this force field. 52 While the detailed architecture of the hexaloop has not yet been solved experimentally, 11,32 our computational prediction and available NMR data cannot be easily reconciled in this case. We suggest that the simulations might be integrated with structural data collected in the future through a reweighting procedure.…”

Conformational Ensembles of Non-Coding Elements in the SARS-CoV-2 Genome from Molecular Dynamics Simulations

“…In one of the two simulations we observe the transient formation of a U200-U205 base-pair capped by a canonical UUCG tetraloop fold [51]. The low population of this state is not surprising, as the canonical UUCG tetraloop fold has been shown not to be stabilised to a sufficient degree within this force-field [52].…”

“…In one of the two simulations we observe the transient formation of a U200-U205 base-pair capped by a canonical UUCG tetraloop fold ( Cheong et al, 1990 ), as also suggested by NMR measurements ( Wacker et al, 2020 ). The low population of this state is not surprising, as this fold has been shown not to be stabilised to a sufficient degree within this force-field ( Mráziková et al, 2020 ).…”

Multiscale Modeling of Phosphate···π Contacts in RNA U-Turns Exposes Differences between Quantum-Chemical and AMBER Force Field Descriptions

“…32−34 It was suggested that these imbalances contribute to an improper dynamical description of r(UNCG) tetraloops and Z-DNA helices during MD simulations. 33,34 Standard van der Waals radii for nucleobase sp 2 carbons were also questioned, and a revision of Lennard-Jones (LJ) parameters of nucleobase atoms in the AFF was advocated. 35 Herein, we investigate the energetics of phosphate•••π contacts using quantum mechanics (QM) calculations with a dispersion-corrected double-hybrid density-functional approximation (DHDF-D3) and symmetry-adapted perturbation theory (SAPT) analysis and compare these results with those obtained by the classical AMBER force field (AFF).…”