Modeling ion-ion interaction in proteins: A molecular dynamics free energy calculation of the guanidinium-acetate association

The twin nitrogen–twin oxygen, C2v association of guanidinium and acetate in water is examined by means of molecular dynamics free energy calculations, using three approaches for handling Coulomb electrostatic interactions: (i) an Ewald lattice summation, (ii) a generalized reaction field correction, and, (iii) a smoothed spherical truncation. The potential of mean force obtained from the Ewald simulation exhibits the expected minima characteristic of a contact and a solvent-separated ion pair. In contrast, the repulsive and, therefore, physically unrealistic profile resulting from a spherical truncation of the electrostatic interactions at 12 A calls into question the validity of such a protocol for simulating charged proteins. The introduction of a generalized reaction field improves the description of the solution significantly, in spite of an artifactual behavior towards the edge of the cutoff sphere. Whereas this approach, compared to a conventional spherical truncation, implies virtually no addition...

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