jp6b03035_si_003.mpg (29.55 MB)
Collision-Induced Dissociation of Electrosprayed Protein Complexes: An All-Atom Molecular Dynamics Model with Mobile Protons
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posted on 2016-05-24, 00:00 authored by Vlad Popa, Danielle
A. Trecroce, Robert G. McAllister, Lars KonermannElectrospray
ionization mass spectrometry (ESI-MS) has become an
indispensable technique for examining noncovalent protein complexes.
Collision-induced dissociation (CID) of these multiply protonated
gaseous ions usually culminates in ejection of a single subunit with
a disproportionately large amount of charge. Experiments suggest that
this process involves subunit unfolding prior to separation from the
residual complex, as well as H+ migration onto the unravelling
chain. Molecular dynamics (MD) simulations are a promising avenue
for gaining detailed insights into these CID events. Unfortunately,
typical MD algorithms do not allow for mobile protons. Here we address
this limitation by implementing a strategy that combines atomistic
force fields (such as OPLS/AA and CHARMM36) with a proton hopping
algorithm, focusing on the tetrameric complexes transthyretin and
streptavidin. Protons are redistributed over all acidic and basic
sites in 20 ps intervals, subject to an energy function that reflects
electrostatic interactions and proton affinities. Our simulations
predict that nativelike conformers at the onset of collisional heating
contain multiple salt bridges. Collisional heating initially causes
subtle structural changes that lead to a gradual decline of these
zwitterionic patterns. Many of the MD runs show gradual unfolding
of a single subunit in conjunction with H+ migration, culminating
in subunit separation from the complex. However, there are also instances
where two or more chains start to unfold simultaneously, giving rise
to charge competition. The scission point where the “winning”
subunit separates from the complex can be attained for different degrees
of unfolding, giving rise to product ions in various charge states.
The simulated product ion distributions are in close agreement with
experimental CID data. Proton enrichment in the departing subunit
is driven by charge–charge repulsion, but the combination of
salt bridge depletion, charge migration, and proton affinity causes
surprising compensation effects among the various energy terms. It
appears that this work provides the most detailed account to date
of the mechanism whereby noncovalent protein complexes disassemble
during CID.
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product ion distributions20 ps intervalsenergy termscollisional heatingMobile Protons Electrospray ionization mass spectrometrycharge competitionCollisional heatingenergy functionnativelike conformersproton affinitiescompensation effectsatomistic force fieldsElectrosprayed Protein Complexescharge migrationsubunit separationproduct ionszwitterionic patternsOPLSproton affinity causesunravelling chainsalt bridge depletionMD algorithmscharge statesProton enrichmentMolecular dynamicssalt bridgestetrameric complexes transthyretinCID eventsCID datanoncovalent protein complexesscission pointCHARMM
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