The H3 loop of antibodies shows unique structural characteristics.

Bojana Popovic,Charlotte M. Deane,Cristian Regep,Jiye Shi,Guy Georges

doi:10.1002/prot.25291

Abstract

ABSTRACTThe 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.

Highlights

Antibodies are an essential part of the immune system
The majority of the affinity and specificity of antibodies is modulated by a set of binding loops called the Complementarity Determining Region (CDR) found on the variable domain of each of the two chains
We find that the H3 loop does not show an increased flexibility

Summary

Introduction

Antibodies are an essential part of the immune system. They are able to attain high specificity and affinity to almost any antigen. A natural human antibody is a symmetric Y shape, each half of the symmetric unit has two chains: a heavy chain (H) and a light (L) chain. The majority of the affinity and specificity of antibodies is modulated by a set of binding loops called the Complementarity Determining Region (CDR) found on the variable domain of each of the two chains. There are six CDR loops, L1, L2, L3 on the light chain and H1, H2, and H3 on the heavy chain. Several definitions of the CDR loops have been proposed; they are based either on sequence variability, contacts with the antigen or structural variability As the central theme of this work is structural variation we use the Chothia structural definition.[1]

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Conclusion