Ions from Solution to the Gas Phase: A Molecular Dynamics Simulation of the Structural Evolution of Substance P during Desolvation of Charged Nanodroplets Generated by Electrospray Ionization.

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 ∼2400 water molecules, 22 hydronium ions, and 10 chloride and contains a single Substance P (SP) [SP + 3H] ion (SP; amino acid sequence RPKPQQFFGLM-NH). 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. SP 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 SP ion and HO and Cl ions. Calculated collision cross sections (CCS) for SP 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 SP ions favor an extended conformation, whereas a compact conformer is favored during the final stages of dehydration.