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

Abstract

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.

Comprehensive Peptide Ion Structure Studies Using Ion Mobility Techniques: Part 3. Relating Solution-Phase to Gas-Phase Structures

“…The droplet then deforms and generates a cone-shaped tail directing the H 3 O + ion toward the vacuum environment. The H 3 O + eventually leaves the droplet bound to cluster of water molecules as observed in a variety of other simulations that investigate the ESI process [35, 37, 40]. …”

“…Therefore, one major benefit of initiating ESI-representative simulations at lower charge state values is that there will be less interruption in such hydrogen bond networks and consequently the surface tension values would be higher (closer to values computed for the water models). The presence of a counter ion such as Cl - inside the droplet can also affect the location of the hydronium ions through a “shielding” effect, again bringing the surface tension values close to those of water models [35]. …”

“…Indeed, it is proposed that the IEM governs the release of charge carrier ions such as Na + and H3O + present on the surface of the droplet during the “shrinkage/fission” stages; this reduces electrostatic repulsion by direct removal of an ion [31, 34–37]. These small charge carriers can leave the droplet in the form of small ionsolvent clusters [34, 35, 37–39]. Konermann et.…”

“…Molecular dynamics (MD) simulations have been widely used to obtain insight into the behavior of the solvent, charge carrier species as well as the protein inside an ESI droplet [35, 37, 40]. In the work described here, extensive MD simulations are employed to examine gas-phase structure establishment by monitoring the fate of the model peptide (Acetyl-PAAAAKAAAAKAAAAKAAAAK) during the late stages of the ESI process and extending to complete dryness and even further sampling of the ions’ dynamics in the gas phase.…”

“…Additionally, these last remaining water molecules act as adducts and do not alter the conformation of the peptide ions [35, 60, 61]. Therefore, in the final stages of the simulation, the last 9 remaining water molecules were eliminated manually in 3 out of 4 repetitions for the charge arrangements of K(6)-K(11)-K(21) and K(6)-K(16)-K(21).…”