Multistate B- to A- transition in protein-DNA Binding - How well is it described by current AMBER force fields?

When DNA interacts with a protein, its structure often undergoes a significant conformational adaptation, usually involving a transition from B-DNA towards the A-DNA form. This is not a two-state, but rather a multistate transition. The A- and B- forms differ mainly in sugar pucker (north/south) and glycosidic torsion χ (/high-).

Dynamic and Nondynamic Electron Correlation Energy Decomposition Based on the Node of the Hartree-Fock Slater Determinant.

Distinguishing between dynamic and nondynamic electron correlation energy is a fundamental concept in quantum chemistry. It can be challenging to make a clear distinction between the two types of correlation energy or to determine their actual contributions in specific cases using wave function theory. This is because both single-reference and multireference methods cover both types of correlation energy to some extent.

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.

Probabilistic Interpretation of NMR -Couplings Determines BI-BII State Equilibria in DNA.

Interpretation of NMR scalar spin-spin coupling constants in DNA becomes more reliable by including distinct structural states such as BI and BII, using the weighted-static or, better still, the recently implemented adiabatic-MD (Ad-MD) method. The calculation method employs an adiabatic ("Ad") dependence of coupling on NMR-assigned torsion angle, ε, weighted by (ε) probability distribution calculated by molecular dynamics (MD). Ad-MD calculations enable cross-validation of the bsc1, OL15, and OL21 force fields and various parametrizations of the Karplus equation describing the dependence of coupling on ε torsion (KE).

The Ad-MD method to calculate NMR shift including effects due to conformational dynamics: The P NMR shift in DNA.

A method for averaging of NMR parameters by molecular dynamics (MD) has been derived from the method of statistical averaging in MD snapshots, benchmarked and applied to structurally dynamic interpretation of the P NMR shift (δ ) in DNA phosphates. The method employs adiabatic dependence of an NMR parameter on selected geometric parameter(s) that is weighted by MD-calculated probability distribution(s) for the geometric parameter(s) (Ad-MD method). The usage of Ad-MD for polymers is computationally convenient when one pre-calculated structural dependence of an NMR parameter is employed for all chemically equivalent units differing only in dynamic behavior.

Z-DNA as a Touchstone for Additive Empirical Force Fields and a Refinement of the Alpha/Gamma DNA Torsions for AMBER.

Although current AMBER force fields are relatively accurate for canonical B-DNA, many noncanonical structures are still described incorrectly. As noncanonical motifs are attracting increasing attention due to the role they play in living organisms, further improvement is desirable. Here, we have chosen the Z-DNA molecule, which can be considered a touchstone of the universality of empirical force fields, since the noncanonical α and γ backbone conformations native to Z-DNA are also found in protein-DNA complexes, i-motif DNA, and other noncanonical DNAs.

Conformational energies and equilibria of cyclic dinucleotides in vacuo and in solution: computational chemistry vs. NMR experiments.

Performance of computational methods in modelling cyclic dinucleotides - an important and challenging class of compounds - has been evaluated by two different benchmarks: (1) gas-phase conformational energies and (2) qualitative agreement with NMR observations of the orientation of the χ-dihedral angle in solvent. In gas-phase benchmarks, where CCSD(T) and DLPNO-CCSD(T) methods have been used as the reference, most of the (dispersion corrected) density functional approximations are accurate enough to justify prioritizing computational cost and compatibility with other modelling options as the criterion of choice. NMR experiments of 3'3'-c-di-AMP, 3'3'-c-GAMP, and 3'3'-c-di-GMP show the overall prevalence of the anti-conformation of purine bases, but some population of syn-conformations is observed for guanines.

Toward Accurate Hydrogen Bonds by Scalable Quantum Monte Carlo.

Single-determinant (SD) fixed-node diffusion Monte Carlo (FNDMC) gains popularity as a benchmark method scalable to large noncovalent systems, although its accuracy limits are not yet fully mapped out. We report on an interesting example of significant SD FNDMC accuracy variations in middle-sized hydrogen-bonded dimer complexes, formic acid (FA) vs methanediol (MD), distinct by the maximum bond order (2 vs 1). While the traditional SD FNDMC schemes based on bias cancellation are capable of achieving benchmark (2%) accuracy for MD, this has not been the case for FA.

RNA Structural Dynamics As Captured by Molecular Simulations: A Comprehensive Overview.

With both catalytic and genetic functions, ribonucleic acid (RNA) is perhaps the most pluripotent chemical species in molecular biology, and its functions are intimately linked to its structure and dynamics. Computer simulations, and in particular atomistic molecular dynamics (MD), allow structural dynamics of biomolecular systems to be investigated with unprecedented temporal and spatial resolution. We here provide a comprehensive overview of the fast-developing field of MD simulations of RNA molecules.

A- to B-DNA Transition in AMBER Force Fields and Its Coupling to Sugar Pucker.

The A/B transition is a basic element of DNA conformational change. Because of its involvement in the sensing of the ionic conditions by DNA and in specific protein-DNA interactions, this transition is important for biological functions of DNA. Therefore, accurate modeling of the A/B equilibrium by means of empirical force fields is of utmost interest.

Mapping the Chemical Space of the RNA Cleavage and Its Implications for Ribozyme Catalysis.

Ribozymes utilize diverse catalytic strategies. We report systematic quantum chemical calculations mapping the catalytic space of RNA cleavage by comparing all chemically feasible reaction mechanisms of RNA self-cleavage, using appropriate model systems including those chemical groups that may directly participate in ribozyme catalysis. We calculated the kinetics of uncatalyzed cleavage reactions proceeding via both monoanionic and dianionic pathways, and explicitly probed effects of various groups acting as general bases (GBs) and/or general acids (GAs), or electrostatic transition state stabilizers.

Noncanonical α/γ Backbone Conformations in RNA and the Accuracy of Their Description by the AMBER Force Field.

The sugar-phosphate backbone of RNA can exist in diverse rotameric substates, giving RNA molecules enormous conformational variability. The most frequent noncanonical backbone conformation in RNA is α/γ = t/t, which is derived from the canonical backbone by a crankshaft motion and largely preserves the standard geometry of the RNA duplex. A similar conformation also exists in DNA, where it has been extensively studied and shown to be involved in DNA-protein interactions.

Adsorption of Organic Molecules to van der Waals Materials: Comparison of Fluorographene and Fluorographite with Graphene and Graphite.

Understanding strength and nature of noncovalent binding to surfaces imposes significant challenge both for computations and experiments. We explored the adsorption of five small nonpolar organic molecules (acetone, acetonitrile, dichloromethane, ethanol, ethyl acetate) to fluorographene and fluorographite using inverse gas chromatography and theoretical calculations, providing new insights into the strength and nature of adsorption of small organic molecules on these surfaces. The measured adsorption enthalpies on fluorographite range from -7 to -13 kcal/mol and are by 1-2 kcal/mol lower than those measured on graphene/graphite, which indicates higher affinity of organic adsorbates to fluorographene than to graphene.

Influence of BII Backbone Substates on DNA Twist: A Unified View and Comparison of Simulation and Experiment for All 136 Distinct Tetranucleotide Sequences.

Reliable representation of the B-DNA base-pair step twist is one of the crucial requirements for theoretical modeling of DNA supercoiling and other biologically relevant phenomena in B-DNA. It has long been suspected that the twist is inaccurately described by current empirical force fields. Unfortunately, comparison of simulation results with experiments is not straightforward because of the presence of BII backbone substates, whose populations may differ in experimental and simulation ensembles.

How to understand atomistic molecular dynamics simulations of RNA and protein-RNA complexes?

We provide a critical assessment of explicit-solvent atomistic molecular dynamics (MD) simulations of RNA and protein/RNA complexes, written primarily for non-specialists with an emphasis to explain the limitations of MD. MD simulations can be likened to hypothetical single-molecule experiments starting from single atomistic conformations and investigating genuine thermal sampling of the biomolecules. The main advantage of MD is the unlimited temporal and spatial resolution of positions of all atoms in the simulated systems.

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

The utility of molecular dynamics (MD) simulations to model biomolecular structure, dynamics, and interactions has witnessed enormous advances in recent years due to the availability of optimized MD software and access to significant computational power, including GPU multicore computing engines and other specialized hardware. This has led researchers to routinely extend conformational sampling times to the microsecond level and beyond. The extended sampling time has allowed the community not only to converge conformational ensembles through complete sampling but also to discover deficiencies and overcome problems with the force fields.

Noncovalent Interactions by Quantum Monte Carlo.

Quantum Monte Carlo (QMC) is a family of stochastic methods for solving quantum many-body problems such as the stationary Schrödinger equation. The review introduces basic notions of electronic structure QMC based on random walks in real space as well as its advances and adaptations to systems with noncovalent interactions. Specific issues such as fixed-node error cancellation, construction of trial wave functions, and efficiency considerations that allow for benchmark quality QMC energy differences are described in detail.

On the Use of Molecular Dynamics Simulations for Probing Allostery through DNA.

A recent study described an allosteric effect in which the binding of a protein to DNA is influenced by another protein bound nearby. The effect shows a periodicity of ∼10 basepairs and decays with increasing protein-protein distance. As a mechanistic explanation, the authors reported a similar periodic, decaying pattern of the correlation coefficient between major groove widths inferred from a shorter molecular dynamics simulation.

Refinement of the Sugar-Phosphate Backbone Torsion Beta for AMBER Force Fields Improves the Description of Z- and B-DNA.

Z-DNA duplexes are a particularly complicated test case for current force fields. We performed a set of explicit solvent molecular dynamics (MD) simulations with various AMBER force field parametrizations including our recent refinements of the ε/ζ and glycosidic torsions. None of these force fields described the ZI/ZII and other backbone substates correctly, and all of them underpredicted the population of the important ZI substate.

Microsecond-Scale MD Simulations of HIV-1 DIS Kissing-Loop Complexes Predict Bulged-In Conformation of the Bulged Bases and Reveal Interesting Differences between Available Variants of the AMBER RNA Force Fields.

We report an extensive set of explicit solvent molecular dynamics (MD) simulations (∼25 μs of accumulated simulation time) of the RNA kissing-loop complex of the HIV-1 virus initiation dimerization site. Despite many structural investigations by X-ray, NMR, and MD techniques, the position of the bulged purines of the kissing complex has not been unambiguously resolved. The X-ray structures consistently show bulged-out positions of the unpaired bases, while several NMR studies show bulged-in conformations.

Modelling of graphene functionalization.

Graphene has attracted great interest because of its remarkable properties and numerous potential applications. A comprehensive understanding of its structural and dynamic properties and those of its derivatives will be required to enable the design and optimization of sophisticated new nanodevices. While it is challenging to perform experimental studies on nanoscale systems at the atomistic level, this is the 'native' scale of computational chemistry.

Mechanical Model of DNA Allostery.

The importance of allosteric effects in DNA is becoming increasingly appreciated, but the underlying mechanisms remain poorly understood. In this work, we propose a general modeling framework to study DNA allostery. We describe DNA in a coarse-grained manner by intra-base pair and base pair step coordinates, complemented by groove widths.

Transferability and additivity of dihedral parameters in polarizable and nonpolarizable empirical force fields.

Recent advances in polarizable force fields have revealed that major reparameterization is necessary when the polarization energy is treated explicitly. This study is focused on the torsional parameters, which are crucial for the accurate description of conformational equilibria in biomolecules. In particular, attention is paid to the influence of polarization on the (i) transferability of dihedral terms between molecules, (ii) transferability between different environments, and (iii) additivity of dihedral energies.

Extensions and applications of the A24 data set of accurate interaction energies.

The A24 data set (Řezáč and Hobza, J. Chem. Theory Comput.

Reactive conformation of the active site in the hairpin ribozyme achieved by molecular dynamics simulations with ε/ζ force field reparametrizations.

X-ray crystallography can provide important insights into the structure of RNA enzymes (ribozymes). However, the details of a ribozyme's active site architecture are often altered by the inactivating chemical modifications necessary to inhibit self-cleavage. Molecular dynamics (MD) simulations are able to complement crystallographic data and model the conformation of the ribozyme's active site in its native form.