Sugar-free antibodies find it harder to function properly
01 Jun 2021
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- Rosie de Laune

 

 

Research from a co-funded ISIS PhD studentship has found that the sugars on antibodies are key to the way they interact with immune receptor cells in the body.

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cartoon representations for 16 of the best-fit immunoglobin IgG1 structures

​Valentina's artwork for the cover of Biophysical Journal; Volume 120, Issue 9

 

A research partnership with UCL has used computational modelling of antibodies alongside Small Angle Neutron and X-ray Scattering (SANS and SAXS) to determine the effect of sugars on their structural behaviour. Antibodies are an important biotherapeutic tool: they can be tailored to treating different diseases, and can direct toxic drugs to the area in the body where they are needed.

Their research, published in Biophysical Journal, looked at the most common class of human antibodies called IgG1. These antibodies are shaped like a 'Y', and act as a bridge: the top two regions, the Fab regions, inte​ract with the foreign material, and the bottom, known as the Fc region, is the part that interacts with your immune system via immune receptors.

This Fc region is bound with sugars, and they are thought to guide the antibody towards the correct receptor, but it's not known how exactly this is done. To try and find out, PhD researcher Valentina Spiteri measured the antibodies with and without sugars on the Sans2D instrument​ at ISIS, the B21 instrument at Diamond Light Source, and analytical ultracentrifuges at UCL.

The different available techniques provide a complementary picture, enabling the team to collect data describing the whole system. Combining the experimental data with a detailed computational modelling study, Valentina produced over 100 best-fit structures, using SASSIE-web, an online web server which streamlines the modelling of SAS data. Valentina was able to see that the sugars hold the Fc region of the antibody in one position, making the crucial interactions with immune cells more favourable. The structures she generated formed the basis of her artwork, which was chosen to feature on the cover of the journal, as shown in the image. ​

Her work is a crucial step not just for understanding the behaviour of antibodies in the body, but also for using the combination of SAXS, SANS and computational modelling to study other biological and chemical systems. In the biological field, the presence of detailed protein structures is a useful starting block for these computational iterations. The main barrier to applying the technique to soft matter studies is often the lack of these starting structures.

The detailed structures gained from crystallography are useful for knowing about part of a system in detail, but by using SAXS and SANS to study the dynamics of the whole system, and both of these approaches using computational modelling, it's possible to gain much more information.

“Often biologists don't have a computational background: I had very little experience writing and using computer code before my PhD, and it was initially intimidating, but I have been able to learn how to use several computational methods and pass this knowledge on to other students and collaborators," explains Valentina.

“Now I have finished my PhD, I hope to stay in research." She adds; “I love the process and the people, and enjoy the mixture of computational and lab-based work. By understanding both the process of protein expression and purification, and the detailed structure, you get to know the system much better."

Her supervisor at ISIS, James Doutch, explains; “Valentina was one of the first persons to use this methodology applied to real-life experiments, and it has been very successful. This is a growing field and really useful for learning how the large, complex, molecules in these systems move and interact with each other."

Her UCL supervisor, Steve Perkins, added; “this was the first time that this type of atomistic modelling has successfully tracked conformational changes that result after a chemical modification to a large protein."

Further information

The full paper can be found online at DOI: 10.1016/j.bpj.2021.02.038

Information on the CCP-SAS project can  be found at www.ccpsas.org

Contact: de Laune, Rosie (STFC,RAL,ISIS)