000829373 001__ 829373 000829373 005__ 20240625095115.0 000829373 0247_ $$2doi$$a10.1021/acs.jpclett.7b00127 000829373 0247_ $$2WOS$$aWOS:000396975600001 000829373 0247_ $$2altmetric$$aaltmetric:16669076 000829373 0247_ $$2pmid$$apmid:28207277 000829373 037__ $$aFZJ-2017-03086 000829373 041__ $$aEnglish 000829373 082__ $$a530 000829373 1001_ $$00000-0002-8220-049X$$aLi, Jinyu$$b0 000829373 245__ $$aProton Dynamics in Protein Mass Spectrometry 000829373 260__ $$aWashington, DC$$bACS$$c2017 000829373 3367_ $$2DRIVER$$aarticle 000829373 3367_ $$2DataCite$$aOutput Types/Journal article 000829373 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1493715921_11152 000829373 3367_ $$2BibTeX$$aARTICLE 000829373 3367_ $$2ORCID$$aJOURNAL_ARTICLE 000829373 3367_ $$00$$2EndNote$$aJournal Article 000829373 520__ $$aNative electrospray ionization/ion mobility-mass spectrometry (ESI/IM-MS) allows an accurate determination of low-resolution structural features of proteins. Yet, the presence of proton dynamics, observed already by us for DNA in the gas phase, and its impact on protein structural determinants, have not been investigated so far. Here, we address this issue by a multistep simulation strategy on a pharmacologically relevant peptide, the N-terminal residues of amyloid-β peptide (Aβ(1–16)). Our calculations reproduce the experimental maximum charge state from ESI-MS and are also in fair agreement with collision cross section (CCS) data measured here by ESI/IM-MS. Although the main structural features are preserved, subtle conformational changes do take place in the first ∼0.1 ms of dynamics. In addition, intramolecular proton dynamics processes occur on the picosecond-time scale in the gas phase as emerging from quantum mechanics/molecular mechanics (QM/MM) simulations at the B3LYP level of theory. We conclude that proton transfer phenomena do occur frequently during fly time in ESI-MS experiments (typically on the millisecond time scale). 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