Structures and Dynamics of DNA Mini-Dumbbells Are Force Field Dependent

Abstract

Flexible nucleic acid structures can be challenging to accurately resolve with currently available experimental structural determination techniques. As an alternative, molecular dynamics (MD) simulations can provide a window into understanding the unique dynamics and population distributions of these biomolecules. Previously, molecular dynamics simulations of noncanonical (non-duplex) nucleic acids have proven difficult to accurately model. With a new influx of improved nucleic acid force fields, achieving an in-depth understanding of the dynamics of flexible nucleic acid structures may be achievable. In this project, currently available nucleic acid force fields are evaluated using a flexible yet stable model system: the DNA mini-dumbbell. Prior to MD simulations, nuclear magnetic resonance (NMR) re-refinement was accomplished using improved refinement techniques in explicit solvent to yield DNA mini-dumbbell structures with better agreement between the newly determined PDB snapshots, with the NMR data itself, as well as the unrestrained simulation data. Starting from newly determined structures, a total aggregate of over 800 μs of production data between 2 DNA mini-dumbbell sequences and 8 force fields was collected to compare to these newly refined structures. The force fields tested spanned from traditional Amber force fields: bsc0, bsc1, OL15, and OL21 to Charmm force fields: Charmm36 and the Drude polarizable force field, as well as force fields from independent developers: Tumuc1 and CuFix/NBFix. The results indicated slight variations not only between the different force fields but also between the sequences as well. Given our previous experiences with high populations of potentially anomalous structures in RNA UUCG tetraloops and in various tetranucleotides, we expected the mini-dumbbell system to be challenging to accurately model. Surprisingly, many of the recently developed force fields generated structures in good agreement with experiments. Yet, each of the force fields provided a different distribution of potentially anomalous structures.

Assessment of A- to B- DNA Transitions Utilizing the Drude Polarizable Force Field

“…This finding highlights both the influence of the Charmm-Gui initialization protocols on production with the Drude FF and the tendency for the Drude FF to overstabilize incorrectly minimized structures for multiple microseconds of production. The latter phenomena was also observed with sampling of DNA mini-dumbbell structures in which a minimized structure that violated the NMR NOEs was maintained for 5 μs in each of the 5 independent replicas . Regardless of how Charmm-Gui minimizes the nucleic acid, the Drude FF does not facilitate a transition back toward the experimentally measured structure, and thus, erroneous structures are maintained during production.…”

Assessing the Current State of Amber Force Field Modifications for DNA─2023 Edition

“…There is no flawless force field, and it is doubtful that there will be a universal force field able to characterize the vast structural diversity existing in biopolymers. Though inclusion of polarization terms has allowed for the dynamic distributions of electronic charge over time and this may lead to an improved force field, it is accompanied by a significant computational cost. , Consideration of the results shown here suggest that Amber force field OL21 with the OPC water model better matches the NMR DDD structure as well as consistently models various double-stranded DNA systemsincluding noncanonical Z-DNAwith increased accuracy than other force field options when compared to the experimental data. The force field exhibits advancements over previous generations, though there is space for continued improvement in terms of addressing variables such as terminal base pair fraying, stacking, and modeling noncanonical DNA structures.…”

“…The overstacking present, though notably mild, requires more work to be done to investigate the potential sequence dependence of base pair stacking in double-stranded nucleic acid systems. Experimentally accurate description of base pair stacking is an ever-present issue in all the force fields evaluated hereparm99-based force fields with varying results − and Tumuc1 overstabilizing base pair stacking compared to the experiment. , Possible solutions may lie in the refinement of glycosidic terms or adjustments in partial charge distributions, but further investigation is needed to address this characteristic that is critical to nucleic acid helical stability.…”

Computational Probing of the Folding Mechanism of Human Telomeric G-Quadruplex DNA

“…However, although some key features of htel GQ folding events were identified in these experimental studies, no comprehensive folding model for htel GQ has been established. Molecular dynamics (MD) simulation provides a promising alternative means of resolving outstanding issues in GQ folding − and of refining structural ensembles of nucleic acids. , Unfortunately, the GQ folding of htel DNAs occurs slowly (over seconds to hours in solution). Thus, its time scale is beyond the practical limit of the conventional all-atom MD simulation protocols.…”