Harbison, Aoife M. and Fadda, Elisa (2019) An atomistic perspective on ADCC quenching by core-fucosylation of IgG1 Fc Nglycans from enhanced sampling molecular dynamics. Glycobiology, 30 (6). pp. 407-414. ISSN 0959-6658

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Abstract

The immunoglobulin type G (IgG) Fc N-glycans are known to modulate the interaction with membrane-bound Fc γ receptors (FcγRs), fine-tuning the antibody’s effector function in a sequence-dependent manner. Particularly interesting in this respect are the roles of galactosylation, which levels are linked to autoimmune conditions and aging, of core fucosylation, which is known to reduce significantly the antibody-dependent cellular cytotoxicity (ADCC), and of sialylation, which also reduces ADCC but only in the context of core-fucosylation. In this work we provide an atomistic level perspective through enhanced sampling computer simulations, based on replica exchange molecular dynamics (REMD), to understand the molecular determinants linking the Fc N-glycans sequence to the observed IgG1 function. Our results indicate that the two symmetrically opposed N-glycans interact extensively through their core trimannose residues. At room temperature the terminal galactose on the α(1-6) arm is restrained to the protein through a network of interactions that keep the arm outstretched, meanwhile the α(1-3) arm extends towards the solvent where a terminal sialic acid remains fully accessible. We also find that the presence of core fucose interferes with the extended sialylated α(1-3) arm, altering its conformational propensity and as a consequence of steric hindrance, significantly enhancing the Fc dynamics. Furthermore, structural analysis shows that the core fucose position within the Fc core obstructs the access of N162 glycosylated FcγRs very much like a “door-stop”, potentially decreasing the IgG/ FcγR binding free energy. All of these factors could represent important clues to understand at the molecular level the dramatic reduction of ADCC as a result of core fucosylation and provide an atomistic level-of-detail framework for the design of high potency IgG1 Fc Nglycoforms.

Item Type:	Article
Additional Information:	This is the preprint version of the published article, which is available at Aoife Harbison, Elisa Fadda, An atomistic perspective on antibody-dependent cellular cytotoxicity quenching by core-fucosylation of IgG1 Fc N-glycans from enhanced sampling molecular dynamics, Glycobiology, Volume 30, Issue 6, June 2020, Pages 407–414, https://doi.org/10.1093/glycob/cwz101 . The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license https://creativecommons.org/licenses/by-nc-nd/4.0/
Keywords:	IgG; N-glycans; core-fucose; FcγRs; ADCC; effector function; mAb; MD; enhanced sampling; REMD;
Academic Unit:	Faculty of Science and Engineering > Chemistry Faculty of Science and Engineering > Research Institutes > Hamilton Institute
Item ID:	13487
Identification Number:	https://doi.org/10.1101/701896
Depositing User:	Elisa Fadda
Date Deposited:	04 Nov 2020 16:36
Journal or Publication Title:	Glycobiology
Publisher:	Oxford University Press
Refereed:	Yes
URI:	Publisher Organisation
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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