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

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 dT, dA, and rA 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