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

• Published in: Journal of chemical theory and computation Vol. 17; no. 4; pp. 2530 - 2540
• Main Authors: Grotz, Kara K, Cruz-León, Sergio, Schwierz, Nadine
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 13.04.2021
• Subjects: Activity coefficients; Binding sites; Biomolecular Systems; Diffusion coefficient; Fluid dynamics; Free energy; Hydration; Ions - chemistry; Magnesium - chemistry; Magnesium chloride; Mathematical models; Molecular dynamics; Molecular Dynamics Simulation; Optimization; Oxygen - chemistry; Parameterization; Parameters; Phosphates - chemistry; Physical simulation; RNA - chemistry; Self diffusion; Simulation; Solvation; Solvents - chemistry; Thermodynamic properties; Thermodynamics; Time; Water - chemistry
• ISSN: 1549-9618; 1549-9626
• DOI: 10.1021/acs.jctc.0c01281

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.