(Graph Presented) Molecular dynamics simulations demonstrate that differences in the interaction of sodium and potassium with the carboxylate side chains of α-poly-L-glutamate (α-PGA) have a dramatic effect on the conformational properties of the polypeptide. Potassium ions cluster mainly in the second and third solvation shells of α-PGA because their low charge density makes the electrostatic interactions between them and α-PGA too weak for K+ to compete with water for the first solvation shell of the α-PGA glutamic acid residuals. Unlike sodium ions, they do not switch the conformation of α-PGA from extended to α-helical. Potentials of mean force for pure water, sodium ion solutions, and potassium ion solutions show marked differences in ion association behavior. This supports the idea that Hofmeister effects depend upon direct ion-macromolecule interactions as well as interactions with water molecules in the first solvation shell rather than bulk water structuring.