Proton Dynamics in Protein Mass Spectrometry.

Area of Science:

• Biophysics
• Computational Chemistry
• Mass Spectrometry

Background:

• Native electrospray ionization/ion mobility-mass spectrometry (ESI/IM-MS) provides low-resolution protein structural information.
• Proton dynamics in gas-phase biomolecules, previously observed in DNA, remain unexplored for proteins.
• Understanding these dynamics is crucial for interpreting ESI-MS data.

Purpose of the Study:

• To investigate the impact of proton dynamics on the structural determinants of amyloid-β peptide (Aβ(1-16)) during ESI/IM-MS.
• To simulate and analyze the conformational changes and proton transfer events in gas-phase peptides.
• To correlate simulation results with experimental ESI/IM-MS data.

Main Methods:

• Multistep simulation strategy applied to Aβ(1-16).
• Quantum mechanics/molecular mechanics (QM/MM) simulations at the B3LYP level of theory.
• Comparison of calculated maximum charge states and collision cross section (CCS) data with experimental ESI/IM-MS measurements.

Main Results:

• Simulations accurately reproduced experimental maximum charge states and agreed with CCS data.
• Subtle conformational changes were observed within the first ~0.1 ms of dynamics.
• Intramolecular proton dynamics occurred on the picosecond timescale in the gas phase.

Conclusions:

• Proton transfer phenomena are frequent during the typical millisecond timescale of ESI-MS experiments.
• These proton transfer events do not significantly alter the main structural determinants of the peptide.
• The study provides insights into gas-phase proton dynamics and their limited effect on protein structure determination by ESI/IM-MS.