Aroop Sircar - Toward high-resolution homology modeling of antibody FV regions and application to antibody-antigen docking

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      Publication Details (including relevant citation   information):

      Arvind Sivasubramanian, Aroop Sircar, Sid Chaudhury, Jeffrey J.   Gray

      Proteins 74(2), 497-514, November 4, 2008.


      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   VL-VH 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.

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