Magnesium force fields for OPC water with accurate solvation, ion-binding, and water-exchange properties: Successful transfer from SPC/E.

Magnesium plays a vital role in a large variety of biological processes. To model such processes by molecular dynamics simulations, researchers rely on accurate force field parameters for Mg2+ and water. OPC is one of the most promising water models yielding an improved description of biomolecules in water. The aim of this work is to provide force field parameters for Mg2+ that lead to accurate simulation results in combination with OPC water. Using 12 different Mg2+ parameter sets that were previously optimized with different water models, we systematically assess the transferability to OPC based on a large variety of experimental properties. The results show that the Mg2+ parameters for SPC/E are transferable to OPC and closely reproduce the experimental solvation free energy, radius of the first hydration shell, coordination number, activity derivative, and binding affinity toward the phosphate oxygens on RNA. Two optimal parameter sets are presented: MicroMg yields water exchange in OPC on the microsecond timescale in agreement with experiments. NanoMg yields accelerated exchange on the nanosecond timescale and facilitates the direct observation of ion binding events for enhanced sampling purposes.

Extended magnesium and calcium force field parameters for accurate ion-nucleic acid interactions in biomolecular simulations.

Magnesium and calcium play an essential role in the folding and function of nucleic acids. To correctly describe their interactions with DNA and RNA in biomolecular simulations, an accurate parameterization is crucial. In most cases, the ion parameters are optimized based on a set of experimental solution properties such as solvation free energies, radial distribution functions, water exchange rates, and activity coefficient derivatives. However, the transferability of such bulk-optimized ion parameters to quantitatively describe biomolecular systems is limited. Here, we extend the applicability of our previous bulk-optimized parameters by including experimental binding affinities toward the phosphate oxygen on nucleic acids. In particular, we systematically adjust the combination rules that are an integral part of the pairwise interaction potentials of classical force fields. This allows us to quantitatively describe specific ion binding to nucleic acids without changing the solution properties in the most simple and efficient way. We show the advancement of the optimized Lorentz combination rule for two representative nucleic acid systems. For double-stranded DNA, the optimized combination rule for Ca2+ significantly improves the agreement with experiments, while the standard combination rule leads to unrealistically distorted DNA structures. For the add A-riboswitch, the optimized combination rule for Mg2+ improves the structure of two specifically bound Mg2+ ions as judged by the experimental distance to the binding site. Including experimental binding affinities toward specific ion binding sites on biomolecules, therefore, provides a promising perspective to develop a more accurate description of metal cations for biomolecular simulations.

Ion-Specific and pH-Dependent Hydration of Mica-Electrolyte Interfaces.

Hydration forces play a crucial role in a wide range of phenomena in physics, chemistry, and biology. Here, we study the hydration of mica surfaces in contact with various alkali chloride solutions over a wide range of concentrations and pH values. Using atomic force microscopy and molecular dynamics simulations, we demonstrate that hydration forces consist of a superposition of a monotonically decaying and an oscillatory part, each with a unique dependence on the specific type of cation. The monotonic hydration force gradually decreases in strength with decreasing bulk hydration energy, leading to a transition from an overall repulsive (Li+, Na+) to an attractive (Rb+, Cs+) force. The oscillatory part, in contrast, displays a binary character, being hardly affected by the presence of strongly hydrated cations (Li+, Na+), but it becomes completely suppressed in the presence of weakly hydrated cations (Rb+, Cs+), in agreement with a less pronounced water structure in simulations. For both aspects, K+ plays an intermediate role, and decreasing pH follows the trend of increasing Rb+ and Cs+ concentrations.

Optimized Magnesium Force Field Parameters for Biomolecular Simulations with Accurate Solvation, Ion-Binding, and Water-Exchange Properties in SPC/E, TIP3P-fb, TIP4P/2005, TIP4P-Ew, and TIP4P-D.

Magnesium is essential in many vital processes. To correctly describe Mg2+ in physiological processes by molecular dynamics simulations, accurate force fields are fundamental. Despite the importance, force fields based on the commonly used 12-6 Lennard-Jones potential showed significant shortcomings. Recently progress was made by an optimization procedure that implicitly accounts for polarizability. The resulting microMg and nanoMg force fields (J. Chem. Theory Comput. 2021, 17, 2530-2540) accurately reproduce a broad range of experimental solution properties and the binding affinity to nucleic acids in TIP3P water. Since countless simulation studies rely on available water models and ion force fields, we here extend the optimization and provide Mg2+ parameters in combination with the SPC/E, TIP3P-fb, TIP4P/2005, TIP4P-Ew, and TIP4P-D water models. For each water model, the Mg2+ force fields reproduce the solvation free energy, the distance to oxygens in the first hydration shell, the hydration number, the activity coefficient derivative in MgCl2 solutions, and the binding affinity and distance to the phosphate oxygens on nucleic acids. We present two parameter sets: MicroMg yields water exchange on the microsecond time scale and matches the experimental exchange rate. Depending on the water model, nanoMg yields accelerated water exchange in the range of 106 to 108 exchanges per second. The nanoMg parameters can be used to enhance the sampling of binding events, to obtain converged distributions of Mg2+, or to predict ion binding sites in biomolecular simulations. The parameter files are freely available at https://github.com/bio-phys/optimizedMgFFs.

Optimized Magnesium Force Field Parameters for Biomolecular Simulations with Accurate Solvation, Ion-Binding, and Water-Exchange Properties.

Magnesium ions play an essential role in many vital processes. To correctly describe their interactions in molecular dynamics simulations, an accurate parametrization is crucial. Despite the importance and considerable scientific effort, current force fields based on the commonly used 12-6 Lennard-Jones interaction potential fail to reproduce a variety of experimental solution properties. In particular, no parametrization exists so far that simultaneously reproduces the solvation free energy and the distance to the water oxygens in the first hydration shell. Moreover, current Mg2+ force fields significantly underestimate the rate of water exchange leading to unrealistically slow exchange kinetics. In order to make progress in the development of improved models, we systematically optimize the Mg2+ parameters in combination with the TIP3P water model in a much larger parameter space than previously done. The results show that a long-ranged interaction potential and modified Lorentz-Berthelot combination rules allow us to accurately reproduce multiple experimental properties including the solvation free energy, the distances to the oxygens of the first hydration shell, the hydration number, the activity coefficient derivative in MgCl2 solutions, the self-diffusion coefficient, and the binding affinity to the phosphate oxygen of RNA. Matching this broad range of thermodynamic properties, we present two sets of optimal parameters: MicroMg yields water exchange on the microsecond timescale in agreement with experiments. NanoMg yields water exchange on the nanosecond timescale facilitating the direct observation of ion-binding events. As shown for the example of the add A-riboswitch, the optimized parameters correctly reproduce the structure of specifically bound ions and permit the de novo prediction of Mg2+-binding sites in biomolecular simulations.

Dispersion Correction Alleviates Dye Stacking of Single-Stranded DNA and RNA in Simulations of Single-Molecule Fluorescence Experiments.

We combine single-molecule Förster resonance energy transfer (single-molecule FRET) experiments with extensive all-atom molecular dynamics (MD) simulations (>100 µs) to characterize the conformational ensembles of single-stranded (ss) DNA and RNA in solution. From MD simulations with explicit dyes attached to single-stranded nucleic acids via flexible linkers, we calculate FRET efficiencies and fluorescence anisotropy decays. We find that dispersion-corrected water models alleviate the problem of overly abundant interactions between fluorescent dyes and the aromatic ring systems of nucleobases. To model dye motions in a computationally efficient and conformationally exhaustive manner, we introduce a dye-conformer library, built from simulations of dinucleotides with covalently attached dye molecules. We use this library to calculate FRET efficiencies for dT19, dA19, and rA19 simulated without explicit labels over a wide range of salt concentrations. For end-labeled homopolymeric pyrimidine ssDNA, MD simulations with the parmBSC1 force field capture the overall trend in salt-dependence of single-molecule FRET based distance measurements. For homopolymeric purine ssRNA and ssDNA, the DESRES and parmBSC1 force fields, respectively, provide useful starting points, even though our comparison also identifies clear deviations from experiment.