A mass spectrometry-based modelling workflow for accurate prediction of IgG antibody conformations in the gas phase

Kjetil Hansen; Andy Man Chung Lau; Kevin Giles; James Michael McDonnell; Weston B. Struwe; Brian John Sutton; Anargyros Politis

doi:10.1002/anie.201812018

A mass spectrometry-based modelling workflow for accurate prediction of IgG antibody conformations in the gas phase

Kjetil Hansen, Andy Man Chung Lau, Kevin Giles, James Michael McDonnell, Weston B. Struwe, Brian John Sutton, Anargyros Politis

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Abstract

Immunoglobulins are biomolecules involved in defence against foreign substances. Flexibility is key to their functional properties in relation to antigen binding and receptor interactions. Here we develop an integrative strategy combining ion mobility mass spectrometry (IM-MS) with molecular modelling to study the conformational dynamics of human IgG antibodies. Predictive models of all four human IgG subclasses were assembled and their dynamics sampled in the transition from extended to collapsed state during IM-MS. Our data imply that this collapse of IgG antibodies is related to their intrinsic structural features, including Fab arm flexibility, collapse towards the Fc region, and the length of their hinge regions. The workflow presented here, provides for the first time an accurate structural representation in good agreement with the observed collision cross section for these flexible IgG molecules. These results have implications for studying other non-globular flexible proteins.

Original language	English
Pages (from-to)	17194-17199
Journal	ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume	57
Issue number	52
Early online date	8 Nov 2018
DOIs	https://doi.org/10.1002/anie.201812018
Publication status	Published - 21 Dec 2018

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A Mass-Spectrometry-Based Modelling_HANSEN_Firstonline8November2018_GOLD VoR (CC BY)Final published version, 2.81 MBLicence: CC BY

Cite this

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abstract = "Immunoglobulins are biomolecules involved in defence against foreign substances. Flexibility is key to their functional properties in relation to antigen binding and receptor interactions. Here we develop an integrative strategy combining ion mobility mass spectrometry (IM-MS) with molecular modelling to study the conformational dynamics of human IgG antibodies. Predictive models of all four human IgG subclasses were assembled and their dynamics sampled in the transition from extended to collapsed state during IM-MS. Our data imply that this collapse of IgG antibodies is related to their intrinsic structural features, including Fab arm flexibility, collapse towards the Fc region, and the length of their hinge regions. The workflow presented here, provides for the first time an accurate structural representation in good agreement with the observed collision cross section for these flexible IgG molecules. These results have implications for studying other non-globular flexible proteins.",

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AU - Struwe, Weston B.

AU - Sutton, Brian John

AU - Politis, Anargyros

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A mass spectrometry-based modelling workflow for accurate prediction of IgG antibody conformations in the gas phase

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