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Rational Design of Particle Mesh Ewald Compatible Lennard-Jones Parameters for +2 Metal Cations in Explicit Solvent.

ABSTRACT: Metal ions play significant roles in biological systems. Accurate molecular dynamics (MD) simulations on these systems require a validated set of parameters. Although there are more detailed ways to model metal ions, the nonbonded model, which employs a 12-6 Lennard-Jones (LJ) term plus an electrostatic potential is still widely used in MD simulations today due to its simple form. However, LJ parameters have limited transferability due to different combining rules, various water models and diverse simulation methods. Recently, simulations employing a Particle Mesh Ewald (PME) treatment for long-range electrostatics have become more and more popular owing to their speed and accuracy. In the present work we have systematically designed LJ parameters for 24 +2 metal (M(II)) cations to reproduce different experimental properties appropriate for the Lorentz-Berthelot combining rules and PME simulations. We began by testing the transferability of currently available M(II) ion LJ parameters. The results showed that there are differences between simulations employing Ewald summation with other simulation methods and that it was necessary to design new parameters specific for PME based simulations. Employing the thermodynamic integration (TI) method and performing periodic boundary MD simulations employing PME, allowed for the systematic investigation of the LJ parameter space. Hydration free energies (HFEs), the ion-oxygen distance in the first solvation shell (IOD) and coordination numbers (CNs) were obtained for various combinations of the parameters of the LJ potential for four widely used water models (TIP3P, SPC/E, TIP4P and TIP4PEW). Results showed that the three simulated properties were highly correlated. Meanwhile, M(II) ions with the same parameters in different water models produce remarkably different HFEs but similar structural properties. It is difficult to reproduce various experimental values simultaneously because the nonbonded model underestimates the interaction between the metal ions and water molecules at short range. Moreover, the extent of underestimation increases successively for the TIP3P, SPC/E, TIP4PEW and TIP4P water models. Nonetheless, we fitted a curve to describe the relationship between ? (the well depth) and radius (Rmin/2) from experimental data on noble gases to facilitate the generation of the best possible compromise models. Hence, by targeting different experimental values, we developed three sets of parameters for M(II) cations for three different water models (TIP3P, SPC/E and TIP4PEW). These parameters we feel represent the best possible compromise that can be achieved using the nonbonded model for the ions in combination with simple water models. From a computational uncertainty analysis we estimate that the uncertainty in our computed HFEs is on the order of ±1kcal/mol. Further improvements will require more advanced non-bonded models likely with inclusion of polarization.

SUBMITTER: Li P

PROVIDER: S-EPMC3728907 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Rational Design of Particle Mesh Ewald Compatible Lennard-Jones Parameters for +2 Metal Cations in Explicit Solvent.

Li Pengfei P Roberts Benjamin P BP Chakravorty Dhruva K DK Merz Kenneth M KM

Journal of chemical theory and computation 20130601 6

Metal ions play significant roles in biological systems. Accurate molecular dynamics (MD) simulations on these systems require a validated set of parameters. Although there are more detailed ways to model metal ions, the nonbonded model, which employs a 12-6 Lennard-Jones (LJ) term plus an electrostatic potential is still widely used in MD simulations today due to its simple form. However, LJ parameters have limited transferability due to different combining rules, various water models and diver ...[more]

PMID: 23914143

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Project description:Molecular dynamics (MD) simulations based on atomic models play an important role in the drug-discovery process to screen molecules, estimate binding free energies, and optimize lead compounds in chemical space. Accurate computations of thermodynamic and kinetic properties using MD simulations are highly dependent on the accuracy of the underlying atomic force field. In this context, going beyond the nonpolarizable fixed-charge model by accounting explicitly for induced polarization is highly desirable. The CHARMM polarizable force field based on classical Drude oscillators, in which an auxiliary charged particle is attached via a harmonic spring to its parent nucleus, offers both a computationally convenient and rigorous framework to model explicitly induced electronic polarization in MD simulations. For any molecule of interest, electrostatic partial charges, atomic polarizabilities, and Thole shielding factors, as well as bonded parameters can either be determined from ab initio calculations or ascribed from the knowledge-based library of the CHARMM Generalized force field. While this approach is fairly reliable in general, it is well understood that the overall accuracy of the models with respect to thermodynamic properties such as bulk density, enthalpies, and solvation free energies is particularly sensitive to the nonbonded Lennard-Jones (LJ) parameters. In the present study, we systematically refined the set of LJ parameters for the atom types available in the Drude force field to best match the experimental thermodynamic properties for 416 small druglike organic molecules. To further test the transferability of the optimized parameters, the hydration free energy of 372 molecules was computed. The calculations resulted in a small average error of 0.46 kcal/mol and a Pearson R of 0.9, representing a significant improvement over the additive GAFF force field in our previous study, where an average error of ∼2 kcal/mol was obtained. Such an improvement is consistent with the ability of the polarizable Drude model to more accurately model interactions in different environments. The effort provides a roadmap for the global optimization of force field parameters using experimental data. It is hoped that the present effort will further the application of the Drude polarizable force field in molecular simulations including drug design and discovery.

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Rational Design of Particle Mesh Ewald Compatible Lennard-Jones Parameters for +2 Metal Cations in Explicit Solvent.

Publications

Rational Design of Particle Mesh Ewald Compatible Lennard-Jones Parameters for +2 Metal Cations in Explicit Solvent.

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