van der Waals Parameter Scanning with Amber Nucleic Acid Force Fields: Revisiting Means to Better Capture the RNA/DNA Structure through MD.

Molecular dynamics simulations can be used in combination with experimental techniques to uncover the intricacies of biomolecular structure, dynamics, and the resulting interactions. However, many noncanonical nucleic acid structures have proven to be challenging to replicate in accurate agreement with experimental data, often attributed to known force field deficiencies. A common force field criticism is the handling of van der Waals (vdW) parameters, which have not been updated since the regular use of Ewald's methods became routine. This work dives into the effects of minute vdW radii shifts on RNA tetranucleotide, B-DNA, and Z-DNA model systems described by commonly used Amber force fields. Using multidimensional replica exchange molecular dynamics (M-REMD), the GACC RNA tetranucleotide demonstrated changes in the structural distribution between the NMR minor and anomalous structure populations based on the O2' vdW radii scanning. However, no significant change in the NMR Major conformation population was observed. There were minimal changes in the B-DNA structure but there were more substantial improvements in Z-DNA structural descriptions, specifically with the Tumuc1 force field. This occurred with both LJbb vdW radii adjustments and incorporation of the CUFIX nonbonded parameter modifications. Though the limited vdW modifications tested did not provide a universal fix to the challenge of simulating the various known nucleic acid structures, they do provide direction and a greater understanding for future force field development efforts.

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

Advances in molecular dynamics (MD) software alongside enhanced computational power and hardware have allowed for MD simulations to significantly expand our knowledge of biomolecular structure, dynamics, and interactions. Furthermore, it has allowed for the extension of conformational sampling times from nanoseconds to the microsecond level and beyond. This has not only made convergence of conformational ensembles through comprehensive sampling possible but consequently exposed deficiencies and allowed the community to overcome limitations in the available force fields. The reproducibility and accuracy of the force fields are imperative in order to produce biologically relevant data. The Amber nucleic acid force fields have been used widely since the mid-1980s, and improvement of these force fields has been a community effort with several artifacts revealed, corrected, and reevaluated by various research groups. Here, we focus on the Amber force fields for use with double-stranded DNA and present the assessment of two recently developed force field parameter sets (OL21 and Tumuc1). Extensive MD simulations were performed with six test systems and two different water models. We observe the improvement of OL21 and Tumuc1 compared to previous generations of the Amber DNA force. We did not detect any significant improvement in the performance of Tumuc1 compared to OL21 despite the reparameterization of bonded force field terms in the former; however, we did note discrepancies in Tumuc1 when modeling Z-DNA sequences.

Evaluating the accuracy of the AMBER protein force fields in modeling dihydrofolate reductase structures: misbalance in the conformational arrangements of the flexible loop domains.

Protein flexible loop regions were once thought to be simple linkers between other more functional secondary structural elements. However, as it becomes clearer that these loop domains are critical players in a plethora of biological processes, accurate conformational sampling of 3D loop structures is vital to the advancement of drug design techniques and the overall growth of knowledge surrounding molecular systems. While experimental techniques provide a wealth of structural information, the resolution of flexible loop domains is sometimes low or entirely absent due to their complex and dynamic nature. This highlights an opportunity for de novo structure prediction using in silico methods with molecular dynamics (MDs). This study evaluates some of the AMBER protein force field's (ffs) ability to accurately model dihydrofolate reductase (DHFR) conformations, a protein complex characterized by specific arrangements and interactions of multiple flexible loops whose conformations are determined by the presence or absence of bound ligands and cofactors. Although the AMBER ffs, including ff19SB, studied well model most protein structures with rich secondary structure, results obtained here suggest the inability to significantly sample the expected DHFR loop-loop conformations - of the six distinct protein-ligand systems simulated, a majority lacked consistent stabilization of experimentally derived metrics definitive the three enzyme conformations. Although under-sampling and the chosen ff parameter combinations could be the cause, given past successes with these MD approaches for many protein systems, this suggests a potential misbalance in available ff parameters required to accurately predict the structure of multiple flexible loop regions present in proteins.Communicated by Ramaswamy H. Sarma.