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.

Kara K Grotz,Nadine Schwierz

doi:10.1021/acs.jctc.1c00791

Kara K Grotz, Nadine Schwierz

Open Access

https://doi.org/10.1021/acs.jctc.1c00791

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Abstract

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.

Highlights

Magnesium is the second most abundant intracellular cation.[1]
We present the results from our parameter optimization of Mg2+ in combination with the SPC/E, TIP3Pfb, TIP4P/2005, TIP4P-Ew, and TIP4P-D water models
Our optimization procedure is done in three sequential steps[26] and allows us to reproduce a broad range of thermodynamic properties including 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 of RNA (Tables 3 and 5)

Summary

Introduction

Magnesium is the second most abundant intracellular cation.[1]. It is involved in more than 600 enzymatic reactions[2] and plays a crucial role in vital processes such as ATP hydrolysis,[3] cellular signaling,[2] or the catalytic activity of ribozymes.[4]. (i) No parameter combination existed that simultaneously reproduced the solvation free energy and the size of the first hydration shell.[20,21,23,27] (ii) The parameters yielded too low water exchange rates leading to unrealistically slow exchange kinetics such that transitions from outer to inner sphere binding and back could never be observed on the typical time scale of MD simulations.[28] (iii) The binding affinity of Mg2+ to ion binding sites on biomolecules was overrated significantly.[19,25,29,30] Regarding these shortcomings, the immediate question arises why classical, nonpolarizable Mg2+ force fields fail to provide an accurate description. Possibilities to provide improvement include the use of Received: August 6, 2021 Published: December 9, 2021

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