TY - JOUR
T1 - Accurate structure prediction of CDR H3 loops enabled by a novel structure-based C-terminal constraint
AU - Weitzner, Brian D.
AU - Gray, Jeffrey J.
N1 - Publisher Copyright:
Copyright © 2016 by The American Association of Immunologists, Inc.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - Ab structure prediction has made great strides, but accurately modeling CDR H3 loops remains elusive. Unlike the other five CDR loops, CDR H3 does not adopt canonical conformations and must be modeled de novo. During Antibody Modeling Assessment II, we found that biasing simulations toward kinked conformations enables generating low-root mean square deviation models (Weitzner et al. 2014. Proteins 82: 1611-1623), and since then, we have presented new geometric parameters defining the kink conformation (Weitzner et al. 2015. Structure 23: 302-311). In this study, we use these parameters to develop a new biasing constraint. When applied to a benchmark set of high-quality CDR H3 loops, the average minimum root mean square deviation sampled is 0.93 Å, compared with 1.34 Å without the constraint. We then test the performance of the constrained de novo method for homology modeling and rigid-body docking and present the results for 1) the Antibody Modeling Assessment II targets, 2) the 2009 RosettaAntibody benchmark set, and 3) the high-quality set.
AB - Ab structure prediction has made great strides, but accurately modeling CDR H3 loops remains elusive. Unlike the other five CDR loops, CDR H3 does not adopt canonical conformations and must be modeled de novo. During Antibody Modeling Assessment II, we found that biasing simulations toward kinked conformations enables generating low-root mean square deviation models (Weitzner et al. 2014. Proteins 82: 1611-1623), and since then, we have presented new geometric parameters defining the kink conformation (Weitzner et al. 2015. Structure 23: 302-311). In this study, we use these parameters to develop a new biasing constraint. When applied to a benchmark set of high-quality CDR H3 loops, the average minimum root mean square deviation sampled is 0.93 Å, compared with 1.34 Å without the constraint. We then test the performance of the constrained de novo method for homology modeling and rigid-body docking and present the results for 1) the Antibody Modeling Assessment II targets, 2) the 2009 RosettaAntibody benchmark set, and 3) the high-quality set.
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U2 - 10.4049/jimmunol.1601137
DO - 10.4049/jimmunol.1601137
M3 - Article
C2 - 27872211
AN - SCOPUS:85006982403
SN - 0022-1767
VL - 198
SP - 505
EP - 515
JO - Journal of Immunology
JF - Journal of Immunology
IS - 1
ER -