Toward high-resolution homology modeling of antibody F v regions and application to antibody-antigen docking

Arvind Sivasubramanian, Aroop Sircar, Sidhartha Chaudhury, Jeffrey J Gray

Research output: Contribution to journalArticle

Abstract

High-resolution homology models are useful in structure-based protein engineering applications, especially when a crystallographic structure is unavailable. Here, we report the development and implementation of RosettaAntibody, a protocol for homology modeling of antibody variable regions. The protocol combines comparative modeling of canonical complementarity determining region (CDR) loop conformations and de novo loop modeling of CDR H3 conformation with simultaneous optimization of V L-V H rigid-body orientation and CDR backbone and side-chain conformations. The protocol was tested on a benchmark of 54 antibody crystal structures. The median root mean square deviation (rmsd) of the antigen binding pocket comprised of all the CDR residues was 1.5 Å with 80% of the targets having an rmsd lower than 2.0 Å. The median backbone heavy atom global rmsd of the CDR H3 loop prediction was 1.6, 1.9, 2.4, 3.1, and 6.0 Å for very short (4-6 residues), short (7-9), medium (10-11), long (12-14) and very long (17-22) loops, respectively. When the set of ten top-scoring antibody homology models are used in local ensemble docking to antigen, a moderate-to-high accuracy docking prediction was achieved in seven of fifteen targets. This success in computational docking with high-resolution homology models is encouraging, but challenges still remain in modeling antibody structures for sequences with long H3 loops. This first large-scale antibody-antigen docking study using homology models reveals the level of ''functional accuracy" of these structural models toward protein engineering applications.

Original languageEnglish (US)
Pages (from-to)497-514
Number of pages18
JournalProteins
Volume74
Issue number2
DOIs
StatePublished - Feb 1 2009

Fingerprint

Complementarity Determining Regions
Antigens
Antibodies
Conformations
Protein Engineering
Benchmarking
Structural Models
Crystal orientation
Proteins
Crystal structure
Atoms

Keywords

  • Antibody structure
  • Cdr h3 loop modeling
  • Comparative modeling
  • Ensemble docking
  • Therapeutic antibodies

ASJC Scopus subject areas

  • Biochemistry
  • Structural Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Toward high-resolution homology modeling of antibody F v regions and application to antibody-antigen docking. / Sivasubramanian, Arvind; Sircar, Aroop; Chaudhury, Sidhartha; Gray, Jeffrey J.

In: Proteins, Vol. 74, No. 2, 01.02.2009, p. 497-514.

Research output: Contribution to journalArticle

Sivasubramanian, Arvind ; Sircar, Aroop ; Chaudhury, Sidhartha ; Gray, Jeffrey J. / Toward high-resolution homology modeling of antibody F v regions and application to antibody-antigen docking. In: Proteins. 2009 ; Vol. 74, No. 2. pp. 497-514.
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