Human beta-defensin 2 is a cysteine-rich antimicrobial peptide. In the Crystal state, the N-terminal segment (residues 1-11) exhibits a helical conformation. However, a truncated form, with four amino acids removed from the N-terminus, adopts nonhelical conformations in solution, as shown by NMR. To explore the molecular origins of these different conformations, we performed Hamiltonian replica exchange molecular dynamics simulations of the peptide in solution and in the crystal state. It is found that backbone hydration and specific protein protein interactions are key parameters that determine the peptide conformation. The helical conformation in the crystal state mainly arises from reduced hydration as well as a salt bridge between the peptide and a symmetry related neighboring monomer in the crystal. When the extent of hydration is reduced and the salt bridge is reintroduced artificially, the peptide is successfully folded back to the helical conformation in solution. The findings not: only shed light on the development of accurate force field parameters for protein molecules but also provide practical guidance in the design of functional proteins and peptides.