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.
This work was supported by National Institutes of Health Grant R01 GM078221 (to J.J.G.). Andrew P. Leaver-Fay is supported by National Institutes of Health Grant R01 GM73151, the Extreme Science and Engineering Discovery Environment is supported by National Science Foundation Grant ACI-1053575, and the Maryland Advanced Research Computing Center is supported by the State of Maryland.
The online version of this article contains supplemental material.
- Received July 11, 2016.
- Accepted September 12, 2016.
- Copyright © 2016 by The American Association of Immunologists, Inc.