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Using advanced computational methods to model the binding of antibody complexes: a case study from the coagulation cascade

Rosellen, Martin; (2021) Using advanced computational methods to model the binding of antibody complexes: a case study from the coagulation cascade. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Haemophilia A is a congenital bleeding disorder affecting one in 5,000 to 10,000 males. To prevent symptomatic disease, injections of recombinant factor VIII (FVIII) are administered to compensate for insufficient levels of this essential clotting factor. Patients suffering from a severe form of haemophilia A are at increased risk of forming neutralising antibodies — known as inhibitors — against therapeutic FVIII. A better understanding of the binding characteristics of inhibitors may aid the selection of optimal haemophilia A therapies, lead to the development of new therapeutics that are less antigenic, and support future initiatives in personalised and precision medicine. With this goal in mind, Classical Molecular Dynamics (CMD) in conjunction with Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) free energy calculations, together with enhanced sampling techniques, have been used to investigate interactions and the dynamics of binding site residues of the human inhibitory antibody BO2C11 bound to the C2-domain of factor VIII. In parallel, recombinant bacterial expressions of the C2-domain were initiated with the aim to explore structural changes induced by mutations that abrogate binding as described previously in surface plasmon resonance experiments. Computational binding affinity predictions were generally shown to be in good agreement with experimental findings. Additionally, binding site dynamics were investigated in detail using customized visualization techniques and an interpretable machine learning approach. Nevertheless, CMD simulations were insufficient for gaining insights into structural changes induced by mutations that were determined experimentally to be non-binding, and for exploring the underlying differences between the bound and unbound structures of the FVIII-C2 domain. To this end, Accelerated Molecular Dynamics (AMD) and Umbrella Sampling (US) simulations proved to be appropriate additions to investigate the conformational changes and energetic differences associated with the binding of BO2C11.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Using advanced computational methods to model the binding of antibody complexes: a case study from the coagulation cascade
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10130181
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