TY - JOUR
T1 - Toward high-resolution homology modeling of antibody F v regions and application to antibody-antigen docking
AU - Sivasubramanian, Arvind
AU - Sircar, Aroop
AU - Chaudhury, Sidhartha
AU - Gray, Jeffrey J.
PY - 2009/2/1
Y1 - 2009/2/1
N2 - 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.
AB - 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.
KW - Antibody structure
KW - Cdr h3 loop modeling
KW - Comparative modeling
KW - Ensemble docking
KW - Therapeutic antibodies
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U2 - 10.1002/prot.22309
DO - 10.1002/prot.22309
M3 - Article
C2 - 19062174
AN - SCOPUS:59449096415
SN - 0887-3585
VL - 74
SP - 497
EP - 514
JO - Proteins: Structure, Function and Bioinformatics
JF - Proteins: Structure, Function and Bioinformatics
IS - 2
ER -