Repertoire analysis of antibody CDR-H3 loops suggests affinity maturation does not typically result in rigidification

Jeliazko R. Jeliazkov, Adnan Sljoka, Daisuke Kuroda, Nobuyuki Tsuchimura, Naoki Katoh, Kouhei Tsumoto, Jeffrey J Gray

Research output: Contribution to journalArticle

Abstract

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 recent 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 simulations, revealed a spectrum of changes in flexibility. Our results suggest that rigidification may be just one of many biophysical mechanisms for increasing affinity.

Original languageEnglish (US)
Article number413
JournalFrontiers in Immunology
Volume9
Issue numberMAR
DOIs
StatePublished - Mar 2 2018

Fingerprint

Complementarity Determining Regions
Antibodies
Antibody Binding Sites
Antigens
Antibody Affinity
Antibody Specificity
Molecular Dynamics Simulation
Statistical Factor Analysis
Immunity
Blood Cells
B-Lymphocytes
Research Design
Databases
Mutation

Keywords

  • Affinity maturation
  • Antibody repertoires
  • Complementarity determining regions
  • Conformational flexibility
  • Molecular dynamics simulations
  • Pebble game algorithm
  • Rigidity theory
  • RosettaAntibody

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Repertoire analysis of antibody CDR-H3 loops suggests affinity maturation does not typically result in rigidification. / Jeliazkov, Jeliazko R.; Sljoka, Adnan; Kuroda, Daisuke; Tsuchimura, Nobuyuki; Katoh, Naoki; Tsumoto, Kouhei; Gray, Jeffrey J.

In: Frontiers in Immunology, Vol. 9, No. MAR, 413, 02.03.2018.

Research output: Contribution to journalArticle

Jeliazkov, Jeliazko R. ; Sljoka, Adnan ; Kuroda, Daisuke ; Tsuchimura, Nobuyuki ; Katoh, Naoki ; Tsumoto, Kouhei ; Gray, Jeffrey J. / Repertoire analysis of antibody CDR-H3 loops suggests affinity maturation does not typically result in rigidification. In: Frontiers in Immunology. 2018 ; Vol. 9, No. MAR.
@article{9bf03bb84d4946b081111538a98fe2f9,
title = "Repertoire analysis of antibody CDR-H3 loops suggests affinity maturation does not typically result in rigidification",
abstract = "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 recent homology models of the human peripheral blood cell antibody repertoire using rigidity theory. We found no clear delineation in the flexibility of na{\"i}ve 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 na{\"i}ve antibodies, and the decrease was not as drastic as previously reported. Further analysis, incorporating molecular dynamics simulations, revealed a spectrum of changes in flexibility. Our results suggest that rigidification may be just one of many biophysical mechanisms for increasing affinity.",
keywords = "Affinity maturation, Antibody repertoires, Complementarity determining regions, Conformational flexibility, Molecular dynamics simulations, Pebble game algorithm, Rigidity theory, RosettaAntibody",
author = "Jeliazkov, {Jeliazko R.} and Adnan Sljoka and Daisuke Kuroda and Nobuyuki Tsuchimura and Naoki Katoh and Kouhei Tsumoto and Gray, {Jeffrey J}",
year = "2018",
month = "3",
day = "2",
doi = "10.3389/fimmu.2018.00413",
language = "English (US)",
volume = "9",
journal = "Frontiers in Immunology",
issn = "1664-3224",
publisher = "Frontiers Media S. A.",
number = "MAR",

}

TY - JOUR

T1 - Repertoire analysis of antibody CDR-H3 loops suggests affinity maturation does not typically result in rigidification

AU - Jeliazkov, Jeliazko R.

AU - Sljoka, Adnan

AU - Kuroda, Daisuke

AU - Tsuchimura, Nobuyuki

AU - Katoh, Naoki

AU - Tsumoto, Kouhei

AU - Gray, Jeffrey J

PY - 2018/3/2

Y1 - 2018/3/2

N2 - 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 recent 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 simulations, revealed a spectrum of changes in flexibility. Our results suggest that rigidification may be just one of many biophysical mechanisms for increasing affinity.

AB - 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 recent 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 simulations, revealed a spectrum of changes in flexibility. Our results suggest that rigidification may be just one of many biophysical mechanisms for increasing affinity.

KW - Affinity maturation

KW - Antibody repertoires

KW - Complementarity determining regions

KW - Conformational flexibility

KW - Molecular dynamics simulations

KW - Pebble game algorithm

KW - Rigidity theory

KW - RosettaAntibody

UR - http://www.scopus.com/inward/record.url?scp=85042709109&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042709109&partnerID=8YFLogxK

U2 - 10.3389/fimmu.2018.00413

DO - 10.3389/fimmu.2018.00413

M3 - Article

VL - 9

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

IS - MAR

M1 - 413

ER -