A combined experimental and theoretical study of ion solvation in liquid N-methylacetamide

Abstract

Most current biomolecular simulations are based on potential energy functions that treat the electrostatic energy as a sum of pairwise Coulombic interactions between effective fixed atomic charges. This approximation, in which many-body induced polarization effects are included in an average way, is expected to be satisfactory for a wide range of systems, but less accurate for processes involving the transfer and partition of ions among heterogeneous environments. The limitations of these potential energy functions are perhaps most obvious in studies of ion permeation through membrane channels. In many cases, the pore is so narrow that the permeating ion must shed most of its surrounding water molecules and the large energetic loss due to dehydration must be compensated by coordination with protein atoms. Interactions of cations with protein backbone carbonyl oxygens, in particular, play a critical role in several important biological channels. As a first step toward meeting the challenge of developing an accurate explicit accounting for induced polarization effects, the present work combines experiments and computation to characterize the interactions of alkali and halide ions with N-methylacetamide chosen to represent the peptide bond. From solubility measurements, we extract the solvation free energies of KCl and NaCl in liquid N-methylacetamide. Polarizable models based on the Drude oscillator are then developed and compared with available experimental and ab initio data. The good agreement for a range of structural and thermodynamic properties in the gas and condensed phases suggests that the polarizable models provide an accurate representation of ion-amide interactions in biological systems.

Figure 1

Solubility of NaCl (filled symbols) or KCl (open symbols) as function of the mole fraction of water in liquid NMA.

Figure 2

Radial distribution functions (RDFs) of solvent around the ions (a–c) and the coordination number distribution (d–f). (a) RDF of O–K⁺. (b) RDF of O–Na⁺. (c) RDF of H–Cl⁻. (d) Coordination number (N_c) of K⁺ in liquid NMA. (e) Coordination number (N_c) of Na⁺ in liquid NMA. (f) Coordination number (Nc) of Cl⁻ in liquid NMA.

Figure 3

Solvation in the reduced models of one to eight ligands. Relative K⁺ and Na⁺ free energy of hydration in the gas phase as a function of the number of ligands in the cluster from simulations with both nonpolarizable and polarizable force fields.