Hydrogen bonding constrains free radical reaction dynamics at serine and threonine residues in peptides

Daniel A. Thomas, Chang Ho Sohn, Jinshan Gao, J. L. Beauchamp

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Free radical-initiated peptide sequencing (FRIPS) mass spectrometry derives advantage from the introduction of highly selective low-energy dissociation pathways in target peptides. An acetyl radical, formed at the peptide N-terminus via collisional activation and subsequent dissociation of a covalently attached radical precursor, abstracts a hydrogen atom from diverse sites on the peptide, yielding sequence information through backbone cleavage as well as side-chain loss. Unique free-radical-initiated dissociation pathways observed at serine and threonine residues lead to cleavage of the neighboring N-terminal Cα-C or N-Cα bond rather than the typical Cα-C bond cleavage observed with other amino acids. These reactions were investigated by FRIPS of model peptides of the form AARAAAXAA, where X is the amino acid of interest. In combination with density functional theory (DFT) calculations, the experiments indicate the strong influence of hydrogen bonding at serine or threonine on the observed free radical chemistry. Hydrogen bonding of the side-chain hydroxyl group with a backbone carbonyl oxygen aligns the singly occupied π orbital on the β-carbon and the N-Cα bond, leading to low-barrier β-cleavage of the N-Cα bond. Interaction with the N-terminal carbonyl favors a hydrogen-atom transfer process to yield stable c and Z ions, whereas C-terminal interaction leads to effective cleavage of the Cα-C bond through rapid loss of isocyanic acid. Dissociation of the Cα-C bond may also occur via water loss followed by β-cleavage from a nitrogen-centered radical. These competitive dissociation pathways from a single residue illustrate the sensitivity of gas-phase free radical chemistry to subtle factors such as hydrogen bonding that affect the potential energy surface for these low-barrier processes.

Original languageEnglish
Pages (from-to)8380-8392
Number of pages13
JournalJournal of Physical Chemistry A
Volume118
Issue number37
DOIs
StatePublished - 18 Sep 2014

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Free radical reactions
Threonine
free radicals
Serine
peptides
cleavage
Hydrogen bonds
Free Radicals
Peptides
dissociation
hydrogen
sequencing
amino acids
Hydrogen
hydrogen atoms
chemistry
water loss
Amino Acids
Atoms
Potential energy surfaces

Cite this

Thomas, Daniel A. ; Sohn, Chang Ho ; Gao, Jinshan ; Beauchamp, J. L. / Hydrogen bonding constrains free radical reaction dynamics at serine and threonine residues in peptides. In: Journal of Physical Chemistry A. 2014 ; Vol. 118, No. 37. pp. 8380-8392.
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Hydrogen bonding constrains free radical reaction dynamics at serine and threonine residues in peptides. / Thomas, Daniel A.; Sohn, Chang Ho; Gao, Jinshan; Beauchamp, J. L.

In: Journal of Physical Chemistry A, Vol. 118, No. 37, 18.09.2014, p. 8380-8392.

Research output: Contribution to journalArticle

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