Epitopes of Protein Binders Are Related to the Structural Flexibility of a Target Protein Surface

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Protein binders including antibodies are known not to bind to random sites of target proteins, and their functional effectiveness mainly depends on the binding region, called the epitope. For the development of protein binders with desired functions, it is thus critical to understand which surface region protein binders prefer (or do not prefer) to bind. The current methods for epitope prediction focus on static indicators such as structural geometry or amino acid propensity, whereas protein binding events are in fact a consequence of dynamic interactions. Here, we demonstrate that the preference for a binding site by protein binders is strongly related to the structural flexibility of a target protein surface. Molecular dynamics simulations on unbound forms of antigen structures revealed that the antigen surface in direct contact with antibodies is less flexible than the rest of the surface. This tendency was shown to be similar in other non-antibody protein binders such as affibody, DARPin, monobody, and repebody. We also found that the relatedness of epitopes to the structural flexibility of a target protein surface is dependent on the secondary structure elements of paratopes. Monobody and repebody, whose binding sites are composed of beta-strands, distinctively prefer to bind to a relatively more rigid region of a target protein. These observations enabled us to develop a simple epitope prediction method which shows a comparable performance to the commonly used ones.
Publisher
AMER CHEMICAL SOC
Issue Date
2021-04
Language
English
Article Type
Article
Citation

JOURNAL OF CHEMICAL INFORMATION AND MODELING, v.61, no.4, pp.2099 - 2107

ISSN
1549-9596
DOI
10.1021/acs.jcim.0c01397
URI
http://hdl.handle.net/10203/285309
Appears in Collection
BS-Journal Papers(저널논문)
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