Imperial College London
Portrait Picture

Professor Cleo Kontoravdi

Faculty of Engineering, Department of Chemical Engineering

Professor of Biological Systems Engineering
 
 
 
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Contact

 

+44 (0)20 7594 6655cleo.kontoravdi98 Website

 
 
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Location

 

310ACE ExtensionSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Shmool:2021:10.1039/d1sc02520a,
author = {Shmool, TA and Martin, LK and Bui-Le, L and Moya-Ramirez, I and Kotidis, P and Matthews, RP and Venter, GA and Kontoravdi, C and Polizzi, KM and Hallett, JP},
doi = {10.1039/d1sc02520a},
journal = {Chemical Science},
pages = {9528--9545},
title = {An experimental approach probing the conformational transitions and energy landscape of antibodies: a glimmer of hope for reviving lost therapeutic candidates using ionic liquid},
url = {http://dx.doi.org/10.1039/d1sc02520a},
volume = {12},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Understanding protein folding in different environmental conditions is fundamentally important for predicting protein structures and developing innovative antibody formulations. While the thermodynamics and kinetics of folding and unfolding have been extensively studied by computational methods, experimental methods for determining antibody conformational transition pathways are lacking. Motivated to fill this gap, we prepared a series of unique formulations containing a high concentration of a chimeric immunoglobin G4 (IgG4) antibody with different excipients in the presence and absence of the ionic liquid (IL) choline dihydrogen phosphate. We determined the effects of different excipients and IL on protein thermal and structural stability by performing variable temperature circular dichroism and bio-layer interferometry analyses. To further rationalise the observations of conformational changes with temperature, we carried out molecular dynamics simulations on a single antibody binding fragment from IgG4 in the different formulations, at low and high temperatures. We developed a methodology to study the conformational transitions and associated thermodynamics of biomolecules, and we showed IL-induced conformational transitions. We showed that the increased propensity for conformational change was driven by preferential binding of the dihydrogen phosphate anion to the antibody fragment. Finally, we found that a formulation containing IL with sugar, amino acids and surfactant is a promising candidate for stabilising proteins against conformational destabilisation and aggregation. We hope that ultimately, we can help in the quest to understand the molecular basis of the stability of antibodies and protein misfolding phenomena and offer new candidate formulations with the potential to revive lost therapeutic candidates.
AU  - Shmool,TA
AU  - Martin,LK
AU  - Bui-Le,L
AU  - Moya-Ramirez,I
AU  - Kotidis,P
AU  - Matthews,RP
AU  - Venter,GA
AU  - Kontoravdi,C
AU  - Polizzi,KM
AU  - Hallett,JP
DO  - 10.1039/d1sc02520a
EP  - 9545
PY  - 2021///
SN  - 2041-6520
SP  - 9528
TI  - An experimental approach probing the conformational transitions and energy landscape of antibodies: a glimmer of hope for reviving lost therapeutic candidates using ionic liquid
T2  - Chemical Science
UR  - http://dx.doi.org/10.1039/d1sc02520a
UR  - https://pubs.rsc.org/en/content/articlelanding/2021/SC/D1SC02520A#!divAbstract
UR  - http://hdl.handle.net/10044/1/89854
VL  - 12
ER  -
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