Molecular dynamics (MD) simulations are used to model changes in the conformational preferences of a model peptide during the transition from a hydrated environment (charged nanodroplet generated by electrospray ionization) to the solvent-free peptide ion. The charged droplet consists of similar to 2400 water molecules, 22 hydronium ions, and 10 chloride and contains a single Substance P (SP) [SP + 3H](3+) ion (SP3+; amino acid sequence RPKPQQFFGLM-NH2). Initially, droplet shrinkage involves a combination of solvent evaporation and ejection of excess charge, primarily hydronium ions. Further droplet shrinkage leads to a series of fission events, which includes the loss of some Cl- ions. SP3+ ions adapt to the smaller size droplet through small conformational changes that result in coiling of the hydrophobic C-terminus of the peptide on or near the droplet surface, intramolecular interactions involving the hydrophilic N-terminus of the peptide, and water-mediated interactions between the SP3+ ion and H3O+ and Cl- ions. Calculated collision cross sections (CCS) for SP3+ ions at various stages of desolvation are consistent with the results obtained from cryogenic ion mobility-mass spectrometry (cryo-IM-MS) measurements. Specifically, early in the decay of the charged droplet SP3+ ions favor an extended conformation, whereas a compact conformer is favored during the final stages of dehydration.