Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form
As of April 1st VIVO Scientific Profiles will no longer updated for faculty, and the link to VIVO will be removed from the library website. Faculty profile pages will continue to be updated via Interfolio. VIVO will continue being used behind the scenes to update graduate student profiles. Please contact helplib@scripps.edu if you have questions.
How to download citations from VIVO | Alternative profile options

Human germline antibody gene segments encode polyspecific antibodies

Academic Article
uri icon
  • Overview
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

authors

  • Willis, J. R.
  • Briney, Bryan
  • DeLuca, S. L.
  • Crowe Jr., J. E.
  • Meiler, J.

publication date

  • 2013

journal

  • PLoS Computational Biology  Journal

abstract

  • Structural flexibility in germline gene-encoded antibodies allows promiscuous binding to diverse antigens. The binding affinity and specificity for a particular epitope typically increase as antibody genes acquire somatic mutations in antigen-stimulated B cells. In this work, we investigated whether germline gene-encoded antibodies are optimal for polyspecificity by determining the basis for recognition of diverse antigens by antibodies encoded by three VH gene segments. Panels of somatically mutated antibodies encoded by a common VH gene, but each binding to a different antigen, were computationally redesigned to predict antibodies that could engage multiple antigens at once. The Rosetta multi-state design process predicted antibody sequences for the entire heavy chain variable region, including framework, CDR1, and CDR2 mutations. The predicted sequences matched the germline gene sequences to a remarkable degree, revealing by computational design the residues that are predicted to enable polyspecificity, i.e., binding of many unrelated antigens with a common sequence. The process thereby reverses antibody maturation in silico. In contrast, when designing antibodies to bind a single antigen, a sequence similar to that of the mature antibody sequence was returned, mimicking natural antibody maturation in silico. We demonstrated that the Rosetta computational design algorithm captures important aspects of antibody/antigen recognition. While the hypervariable region CDR3 often mediates much of the specificity of mature antibodies, we identified key positions in the VH gene encoding CDR1, CDR2, and the immunoglobulin framework that are critical contributors for polyspecificity in germline antibodies. Computational design of antibodies capable of binding multiple antigens may allow the rational design of antibodies that retain polyspecificity for diverse epitope binding.

subject areas

  • Algorithms
  • Amino Acids
  • Antibodies
  • Antigen-Antibody Complex
  • Antigens
  • Computational Biology
  • Computer Simulation
  • Epitopes
  • Genes, Immunoglobulin
  • Humans
  • Mutation
  • Programming Languages
  • Protein Binding
  • Protein Conformation
  • Software
scroll to property group menus

Identity

PubMed Central ID

  • PMC3636087

International Standard Serial Number (ISSN)

  • 1553-7358

Digital Object Identifier (DOI)

  • 10.1371/journal.pcbi.1003045

PubMed ID

  • 23637590
scroll to property group menus

Additional Document Info

start page

  • e1003045

volume

  • 9

issue

  • 4

©2022 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support