Higher affinity antibodies bind with lower hydration and flexibility in large scale simulations
Higher affinity antibodies bind with lower hydration and flexibility in large scale simulations
We have carried out a long-timescale simulation study on crystal structures of nine antibody-antigen pairs, in antigen-bound and antibody-only forms, using molecular dynamics with enhanced sampling and an explicit water model to explore interface conformation and hydration. By combining atomic level simulation and replica exchange to enable full protein flexibility, we find significant numbers of bridging water molecules at the antibody-antigen interface. Additionally, a higher proportion of interactions excluding
bulk waters and a lower degree of antigen bound CDR conformational sampling are correlated with higher antibody affinity. The CDR sampling supports enthalpically driven antibody binding, as opposed to entropically driven, in that the difference between antigen bound and unbound conformations do not correlate with affinity. We thus propose that interactions with waters and CDR sampling are aspects of the interface that may moderate antibody-antigen binding, and that explicit hydration and CDR flexibility should be considered to improve antibody affinity prediction and computational design workflows.
CDR flexibility, antibody affinity, antibody binding, antibody interface hydration, antibody-antigen interactions, molecular dynamics, replica exchange
Wong, Mabel Tung Yuet
97923566-eaa6-41af-b1af-83bb57d61753
Kelm, Sebastian
2034fb1c-cbac-4aaa-97d6-8dbc08c7537c
Liu, Xiaofeng
8680eea1-92c1-4e77-8de5-29bc0691b5d1
Taylor, Richard D.
141004d4-95a6-44f1-93ce-ca36c1b34d61
Baker, Terry
6976cffe-ba5b-4a5f-9d1c-2b44b9f00fb3
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
30 May 2022
Wong, Mabel Tung Yuet
97923566-eaa6-41af-b1af-83bb57d61753
Kelm, Sebastian
2034fb1c-cbac-4aaa-97d6-8dbc08c7537c
Liu, Xiaofeng
8680eea1-92c1-4e77-8de5-29bc0691b5d1
Taylor, Richard D.
141004d4-95a6-44f1-93ce-ca36c1b34d61
Baker, Terry
6976cffe-ba5b-4a5f-9d1c-2b44b9f00fb3
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Wong, Mabel Tung Yuet, Kelm, Sebastian, Liu, Xiaofeng, Taylor, Richard D., Baker, Terry and Essex, Jonathan W.
(2022)
Higher affinity antibodies bind with lower hydration and flexibility in large scale simulations.
Frontiers in Immunology, 13, [884110].
(doi:10.3389/fimmu.2022.884110).
Abstract
We have carried out a long-timescale simulation study on crystal structures of nine antibody-antigen pairs, in antigen-bound and antibody-only forms, using molecular dynamics with enhanced sampling and an explicit water model to explore interface conformation and hydration. By combining atomic level simulation and replica exchange to enable full protein flexibility, we find significant numbers of bridging water molecules at the antibody-antigen interface. Additionally, a higher proportion of interactions excluding
bulk waters and a lower degree of antigen bound CDR conformational sampling are correlated with higher antibody affinity. The CDR sampling supports enthalpically driven antibody binding, as opposed to entropically driven, in that the difference between antigen bound and unbound conformations do not correlate with affinity. We thus propose that interactions with waters and CDR sampling are aspects of the interface that may moderate antibody-antigen binding, and that explicit hydration and CDR flexibility should be considered to improve antibody affinity prediction and computational design workflows.
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More information
Accepted/In Press date: 22 April 2022
Published date: 30 May 2022
Additional Information:
Funding Information:
The authors acknowledge the use of two computing resources in the completion of this work: the IRIDIS High Performance Computing Facility and associated support services at the University of Southampton, and ARCHER granted via the UK High-End Computing Consortium for Biomolecular Simulation (http://hecbiosim.ac.uk).
Funding Information:
MW’s studentship was partially funded by UCB. MW, SK, and RT are employees of UCB. XL and TB were former employees of UCB, and XL is a current employee of AngitiaBio. JE’s research is partially funded by UCB.
Funding Information:
MW thanks the Biotechnology and Biological Sciences Research Council (grant no. BB/P504713/1) and Union Chimique Belge for funding. The ARCHER computing resource was supported by the Engineering and Physical Sciences Research Council (grant no. EP/R029407/1).
Publisher Copyright:
Copyright © 2022 Wong, Kelm, Liu, Taylor, Baker and Essex.
Keywords:
CDR flexibility, antibody affinity, antibody binding, antibody interface hydration, antibody-antigen interactions, molecular dynamics, replica exchange
Identifiers
Local EPrints ID: 472241
URI: http://eprints.soton.ac.uk/id/eprint/472241
ISSN: 1664-3224
PURE UUID: 9c1bbf2d-b2c2-442d-8e44-d51e146308e6
Catalogue record
Date deposited: 30 Nov 2022 17:32
Last modified: 17 Mar 2024 02:40
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Contributors
Author:
Mabel Tung Yuet Wong
Author:
Sebastian Kelm
Author:
Xiaofeng Liu
Author:
Richard D. Taylor
Author:
Terry Baker
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