Development of molecular simulation methods to accurately represent protein-surface interactions: Method assessment for the calculation of electrostatic effects.

The simulation of the interactions of proteins with charged surfaces in a condensed-phase aqueous solution containing electrolytes using empirical force field based methods is predominantly governed by nonbonded interactions between the atoms of the protein, surface, and the solvent. Electrostatic effects represent the strongest type of these interactions and the type that is most difficult to accurately represent because of their long-range influence. While many different methods have been developed to represent electrostatic interactions, the particle mesh Ewald summation (PME) method is generally considered to be the most accurate one for calculating these effects. However, the PME method was designed for systems with three-dimensional (3D) periodicity, and not for interfacial systems such as the case of protein adsorption to a charged surface. Interfacial systems such as these have only two-dimensional periodicity, which may not be appropriate for treatment with PME due to the possibility that the presence of multiple charged image surfaces parallel to the primary simulation cell's surface, may introduce nonphysical effects on the behavior of the charged molecules in the system. In an effort to address this issue, the authors have conducted a set of nanosecond-scale molecular dynamics simulations to calculate the equilibrium distribution of Na(+) and Cl(-) ions near a charged surface using PME and a range of radial cutoff methods for treating electrostatic interactions, where the cutoffs prevent interaction with the periodic images of the system. The resulting ion concentration profiles were compared to one another and to a continuum analytical solution of the theoretical ion distribution obtained from the Poisson-Boltzmann equation. Their results show that the PME method does not introduce the suspected nonphysical effects in the ion distributions due to the 3D periodic images of the system, thus indicating that it is appropriate for use for this type of molecular simulation. Although their interest is motivated by protein-surface interactions, the conclusions are applicable for the treatment of electrostatics in other aqueous systems with two-dimensional periodicity.