Repertoire Analysis of Antibody CDR-H3 Loops Suggests Affinity Maturation Does Not Typically Result in Rigidification

By J. Jeliazkov, Adnan Sljoka, Daisuke Kuroda, Nobuyuki Tsuchimura, Naoki Katoh, K. Tsumoto, Jeffrey J. Gray. 2017

59 citations recorded by the source corpus.

Antibodies can rapidly evolve in specific response to antigens. Affinity maturation drives this evolution through cycles of mutation and selection leading to enhanced antibody specificity and affinity. Elucidating the biophysical mechanisms that underlie affinity maturation is fundamental to understanding B-cell immunity. An emergent hypothesis is that affinity maturation reduces the conformational flexibility of the antibody’s antigen-binding paratope to minimize entropic losses incurred upon binding. In recent years, computational and experimental approaches have tested this hypothesis on a small number of antibodies, often observing a decrease in the flexibility of the Complementarity Determining Region (CDR) loops that typically comprise the paratope and in particular the CDR-H3 loop, which contributes a plurality of antigen contacts. However, there were a few exceptions, and previous studies were limited to a small handful of cases. Here, we determined the structural flexibility of the CDR-H3 loop for thousands of recently-determined homology models of the human peripheral blood cell antibody repertoire using rigidity theory. We found no clear delineation in the flexibility of naïve and antigen-experienced antibodies. To account for possible sources of error, we additionally analyzed hundreds of human and mouse antibodies in the Protein Data Bank through both rigidity theory and B-factor analysis. By both metrics, we observed only a slight decrease in the CDR-H3 loop flexibility when comparing affinity-matured antibodies to naïve antibodies, and the decrease was not as drastic as previously reported. Further analysis, incorporating molecular dynamics (MD) simulations, revealed a spectrum of changes in flexibility. Our results suggest that rigidification may be just one of many biophysical mechanisms for increasing affinity.

Subfields: Molecular Biology, Oncology, Radiology, Nuclear Medicine and Imaging

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Citations in the corpus

Cognizance of Molecular Methods for the Generation of Mutagenic Phage Display Antibody Libraries for Affinity Maturation (2019, methodology): “A recent report employed B-factor analysis to analyze a human peripheral blood antibody repertoire, typically the VH-CDR3 loop, and revealed that affinity maturation does not necessarily cause rigidification [209].”
Multistate design of influenza antibodies improves affinity and breadth against seasonal viruses (2019, background): “It is common that affinityenhancing mutations are located in positions that do not directly contact antigen and function by increasing antibody stability and rigidifying CDR loops (29, 30).”