The H3 loop of antibodies shows unique structural characteristics

• Published in: Proteins, structure, function, and bioinformatics structure, function, and bioinformatics, 2017-07, Vol.85 (7), p.1311-1318
• Main Authors: Regep, Cristian, Georges, Guy, Shi, Jiye, Popovic, Bojana, Deane, Charlotte M.
• Format: Article
• Language: English
• Subjects: Algorithms; Antibodies; Antibodies - chemistry; Antigens; Antigens - chemistry; Binding Sites; CDR H3; Complementarity; Complementarity Determining Regions - chemistry; Fragments; Glycine; Glycine - chemistry; Humans; Immunoglobulin Heavy Chains - chemistry; loop modeling; Protein Binding; Protein Folding; protein loop; Protein Structure, Secondary; Proteins; Software; structural diversity; Temperature; Thermodynamics; Tyrosine; Tyrosine - chemistry
• ISSN: 0887-3585; 1097-0134
• DOI: 10.1002/prot.25291

ABSTRACT The H3 loop in the Complementarity Determining Region of antibodies plays a key role in their ability to bind the diverse space of potential antigens. It is also exceptionally difficult to model computationally causing a significant hurdle for in silico development of antibody biotherapeutics. In this article, we show that most H3s have unique structural characteristics which may explain why they are so challenging to model. We found that over 75% of H3 loops do not have a sub‐Angstrom structural neighbor in the non‐antibody world. Also, in a comparison with a nonredundant set of all protein fragments over 30% of H3 loops have a unique structure, with the average for all of other loops being less than 3%. We further observed that this structural difference can be seen at the level of four residue fragments where H3 loops present numerous novel conformations, and also at the level of individual residues with Tyrosine and Glycine often found in energetically unfavorable conformations. Proteins 2017; 85:1311–1318. © 2017 Wiley Periodicals, Inc.