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Local environment effects on charged mutations for developing aggregation-resistant monoclonal antibodies

Authors
Lee, JihyeonChong, Song-HoHam, Si Hyun
Issue Date
Dec-2020
Publisher
Nature Research
Citation
Scientific Reports, v.10, no.1, pp 1 - 13
Pages
13
Journal Title
Scientific Reports
Volume
10
Number
1
Start Page
1
End Page
13
URI
https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/999
DOI
10.1038/s41598-020-78136-1
ISSN
2045-2322
Abstract
Protein aggregation is a major concern in biotherapeutic applications of monoclonal antibodies. Introducing charged mutations is among the promising strategies to improve aggregation resistance. However, the impact of such mutations on solubilizing activity depends largely on the inserting location, whose mechanism is still not well understood. Here, we address this issue from a solvation viewpoint, and this is done by analyzing how the change in solvation free energy upon charged mutation is composed of individual contributions from constituent residues. To this end, we perform molecular dynamics simulations for a number of antibody mutants and carry out the residue-wise decomposition of the solvation free energy. We find that, in addition to the previously identified “global” principle emphasizing the key role played by the protein total net charge, a local net charge within ∼ 15 Å from the mutation site exerts significant effects. For example, when the net charge of an antibody is positive, the global principle states that introducing a positively charged mutation will lead to more favorable solvation. Our finding further adds that an even more optimal mutation can be done at the site around which more positively charged residues and fewer negatively charged residues are present. Such a “local” design principle accounts for the location dependence of charged mutations, and will be useful in producing aggregation-resistant antibodies. © 2020, The Author(s).
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