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

The twin nitrogen-twin oxygen, C-2v 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 Angstrom 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 additional computational effort, it rapidly becomes costly for large ion-water and water-water cutoff radii. At 12 Angstrom, the computational investment is comparable to that of an Ewald simulation with an appropriately chosen number of k-vectors and separation parameter, making the latter more cost-effective. (C) 2000 American Institute of Physics. [S0021-9606(00)51422-6].