A model beta-hairpin peptide has been used to investigate the context-dependent contribution of cross-strand Lys-Glu interactions to hairpin stability. We have mutated two Ser-Lys interstrand pairs to Glu-Lys salt bridges, one close to the type I' Asn-Gly turn sequence (Ser6 --> Glu), and one close to the N- and C-termini (Ser15 --> Glu). Each individual interaction contributes similar to1.2-1.3 kJ mol(-1) to stability; however, introducing the two salt bridges simultaneously produces a much larger overall contribution (-3.6 kJ mol(-1)) consistent with an important role for preorganization and cooperativity in determining the energetics of weak interactions. We compare and contrast CD and NMR data on the highly folded hairpin with the two Glu-Lys pairs to shed light on the nature of the folded state in water. We show that large cosolvent-induced changes in the CD spectrum, in contrast with the modest effects observed on Halpha chemical shifts, support a hydrophobically collapsed entropy-driven conformation in water whose stability is modulated by long-range Coulombic interactions from the Glu-Lys interactions. Cosolvent stabilizes the structure enthalpically, as is evident from CD melting profiles.