Biology subjects

Kuhrova, P.

Publications and source records attributed to Kuhrova, P..

6 recordsLinked to original sources

bioRxiv2023

Simple Adjustment of Intra-nucleotide Base-phosphate Interaction in OL3 AMBER Force Field Improves RNA Simulations

Molecular dynamics (MD) simulations represent an established tool to study RNA molecules. Outcome of MD studies depends, however, on the quality of the used force field (ff). Here we suggest a correction for the widely used AMBER OL3 ff by adding a simple adjustment of nonbonded parameters. The reparameterization of Lennard-Jones potential for the -H8...O5- and -H6...O5- atom pairs addresses an intra-nucleotide steric clash occurring in the type 0 base-phosphate interaction (0BPh). The non-bonded fix (NBfix) modification of 0BPh interactions (the NBfix0BPh modification) was tuned via reweighting approach and, subsequently, tested using extensive set of standard and enhanced sampling simulations of both unstructured and folded RNA motifs. The modification corrects minor but visible intra-nucleotide clash for the anti nucleobase conformation. We observed that structural ensembles of small RNA benchmark motifs simulated with the NBfix0BPh modification provide better agreement with experiments. No side-effects of the modification were observed in standard simulations of larger structured RNA motifs. We suggest that the combination of OL3 RNA ff and NBfix0BPh modification is a viable option to improve RNA MD simulations.

biophysics↗

bioRxiv2021

Towards Convergence in Folding Simulations of RNA Tetraloops: Comparison of Enhanced Sampling Techniques and Effects of Force Field Corrections

Atomistic molecular dynamics (MD) simulations represent established technique for investigation of RNA structural dynamics. Despite continuous development, contemporary RNA simulations still suffer from suboptimal accuracy of empirical potentials (force fields, ffs) and sampling limitations. Development of efficient enhanced sampling techniques is important for two reasons. First, they allow to overcome the sampling limitations and, second, they can be used to quantify ff imbalances provided they reach a sufficient convergence. Here, we study two RNA tetraloops (TLs), namely the GAGA and UUCG motifs. We perform extensive folding simulations and calculate folding free energies ({Delta}Gfold) with the aim to compare different enhanced sampling techniques and to test several modifications of the nonbonded terms extending the AMBER OL3 RNA ff. We demonstrate that replica exchange solute tempering (REST2) simulations with 12-16 replicas do not show any sign of convergence even when extended to time scale of 120 s per replica. However, combination of REST2 with well-tempered metadynamics (ST-MetaD) achieves good convergence on a time-scale of 5-10 s per replica, improving the sampling efficiency by at least two orders of magnitude. Effects of ff modifications on {Delta}Gfold energies were initially explored by the reweighting approach and then validated by new simulations. We tested several manually-prepared variants of gHBfix potential which improve stability of the native state of both TLs by up to ~2 kcal/mol. This is sufficient to conveniently stabilize the folded GAGA TL while the UUCG TL still remains under-stabilized. Appropriate adjustment of van der Waals parameters for C-H...O5 base-phosphate interaction are also shown to be capable of further stabilizing the native states of both TLs by ~0.6 kcal/mol.

biophysics↗

bioRxiv2020

W-RESP: Well-Restrained Electrostatic Potential Derived Charges. Revisiting the Charge Derivation Model.

Representation of electrostatic interactions by a Coulombic pair-wise potential between atom-centered partial charges is a fundamental and crucial part of empirical force fields used in classical molecular dynamics simulations. The broad success of the AMBER force field family originates mainly from the restrained electrostatic potential (RESP) charge model, which derives partial charges to reproduce the electrostatic field around the molecules. However, description of the electrostatic potential around molecules by standard RESP may be biased for some types of molecules. In this study, we modified the RESP charge derivation model to improve its description of the electrostatic potential around molecules, and thus electrostatic interactions in the force field. In particular, we re-optimized the atomic radii for definition of the grid points around the molecule, redesigned the restraining scheme and included extra point charges. The RESP fitting was significantly improved for aromatic heterocyclic molecules. Thus, the suggested W-RESP(-EP) charge derivation model showed clear potential for improving the performance of the nucleic acid force fields, for which poor description of nonbonded interactions, such as underestimated base pairing, makes it difficult to describe the folding free energy landscape of small oligonucleotides.

biophysics↗

bioRxiv2020

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

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.

biophysics↗

bioRxiv2020

Fine-tuning of the AMBER RNA Force Field with a New Term Adjusting Interactions of Terminal Nucleotides

Determination of RNA structural-dynamic properties is challenging for experimental methods. Thus atomistic molecular dynamics (MD) simulations represent a helpful technique complementary to experiments. However, contemporary MD methods still suffer from limitations of force fields (ffs), including imbalances in the non-bonded ff terms. We have recently demonstrated that some improvement of state-of-the-art AMBER RNA ff can be achieved by adding a new term for H-bonding called gHBfix, which increases tuning flexibility and reduces the risk of side-effects. Still, the first gHBfix version did not fully correct simulations of short RNA tetranucleotides (TNs). TNs are key benchmark systems due to availability of unique NMR data, although giving too much weight on improving TN simulations can easily lead to over-fitting to A-form RNA. Here we combine the gHBfix version with another term called tHBfix, which separately treats H-bond interactions formed by terminal nucleotides. This allows to refine simulations of RNA TNs without affecting simulations of other RNAs. The approach is in line with adopted strategy of current RNA ffs, where the terminal nucleotides possess different parameters for the terminal atoms than the internal nucleotides. The combination of gHBfix with tHBfix significantly improves the behavior of RNA TNs during well-converged enhanced-sampling simulations. TNs mostly populate canonical A-form like states while spurious intercalated structures are largely suppressed. Still, simulations of r(AAAA) and r(UUUU) TNs show some residual discrepancies with the primary NMR data which suggests that future tuning of some other ff terms might be useful.

biophysics↗

bioRxiv2018

IMPROVING THE PERFORMANCE OF THE RNA AMBER FORCE FIELD BY TUNING THE HYDROGEN-BONDING INTERACTIONS

Molecular dynamics (MD) simulations became a leading tool for investigation of structural dynamics of nucleic acids. Despite recent efforts to improve the empirical potentials (force fields, ffs), RNA ffs have persisting deficiencies, which hamper their utilization in quantitatively accurate simulations. Previous studies have shown that at least two salient problems contribute to difficulties in description of free-energy landscapes of small RNA motifs: (i) excessive stabilization of the unfolded single-stranded RNA ensemble by intramolecular base-phosphate and sugar-phosphate interactions, and (ii) destabilization of the native folded state by underestimation of stability of base pairing. Here, we introduce a general ff term (gHBfix) that can selectively fine-tune non-bonding interaction terms in RNA ffs, in particular the H-bonds. gHBfix potential affects the pair-wise interactions between all possible pairs of the specific atom types, while all other interactions remain intact, i.e., it is not a structure-based model. In order to probe the ability of the gHBfix potential to refine the ff non-bonded terms, we performed an extensive set of folding simulations of RNA tetranucleotides and tetraloops. Based on these data we propose particular gHBfix parameters to modify the AMBER RNA ff. The suggested parametrization significantly improves the agreement between experimental data and the simulation conformational ensembles, although our current ff version still remains far from being flawless. While attempts to tune the RNA ffs by conventional reparametrizations of dihedral potentials or non-bonded terms can lead to major undesired side effects as we demonstrate for some recently published ffs, gHBfix has a clear promising potential to improve the ff performance while avoiding introduction of major new imbalances.

biochemistry↗