Year: 2024
Type: dissertation
Abstract: This thesis presents work focusing on antibody structural prediction and structure/sequence analysis. The first section is in the domain of structure prediction. More specifically creating software with the capability to correctly predict a previously defined torsion angle between the $V_{H}$ and $V_{L}$ domains of the antigen binding fragment, which would allow the fine-tuning of predictive models to preserve internal structural geometry. This region is responsible for antigen binding, and thus imperative to model accurately. The software created was named abYpap: `antibody packing-angle predictor' and was an improvement on previously published software. The second section was focused on the relationship of antibody specificity and the geometric flexibility of the $V_{H}$ and $V_{L}$ domains relative to each other. The hypothesis was that an antibody which has gone through more rounds of mutation (and thus achieved higher levels of target specificity and affinity), has a more rigid structure than a less specific (early response) antibody, which may need to bind different antigens and may thus have a more flexible binding region. This was investigated by using the number of replacement mutations from the closest germline as a proxy for the degree of specificity and comparing that with the range of angles a particular antibody shows within its available structures. The conclusion was that there does indeed seem to be a rigidification effect as the antibody mutates from germline. The third section of this body of work focuses on exploiting the large amount of sequence data available for antibodies, to determine if more mature antibodies (those expected to have higher affinity and specificity) contain higher numbers of hydrophobic or hydrophilic residues. This was done by using the number of replacement mutations from an assigned germline as a proxy for the degree of maturation and by comparing the Eisenberg hydrophobicities for the germline and the mature sequence, as well as comparing the number of hydrophobic/hydrophilic residues in the germline as compared to the mature sequences. The data presented here shows an increase in both hydrophobic and hydrophilic residues, and a decrease in amphipathic residues, as the antibody becomes more mature.
Author: Boron, Veronica Anna
Institution: University College London
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7045280202