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.

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exocytosis. We analyze these experimental protocols, derive simple formulas for special cases, and distinguish carefully between the Ca2þ current cooperativity, defined as the exponent in the relationship between exocytosis rate and the Ca2þ current magnitude, and the underlying Ca2þ channel cooperativity, defined as the average number of channels involved in the release of a single vesicle. Further, we use 3D computational modeling of buffered Ca2þ diffusion to analyze the distinct Ca2þ cooperativity measures, and demonstrate the role of endogenous Ca2þ buffers on such measures. We show that buffers can either increase or decrease the calcium current cooperativity of exocytosis, depending on their concentration and calcium-binding properties, and the distance between channel and vesicle.