RT Journal Article
SR Electronic
T1 An Adaptive Geometric Search Algorithm for Macromolecular Scaffold Selection
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 099762
DO 10.1101/099762
A1 Tian Jiang
A1 P. Douglas Renfrew
A1 Kevin Drew
A1 Noah Youngs
A1 Glenn Butterfoss
A1 Dennis Shasha
A1 Richard Bonneau
YR 2017
UL http://biorxiv.org/content/early/2017/01/11/099762.abstract
AB A wide variety of protein and peptidomimetic design tasks require matching functional three-dimensional motifs to potential oligomeric scaffolds. Enzyme design, for example, aims to graft active-site patterns typically consisting of 3 to 15 residues onto new protein surfaces. Identifying suitable proteins capable of scaffolding such active-site engraftment requires costly searches to identify protein folds that can provide the correct positioning of side chains to host the desired active site. Other examples of biodesign tasks that require simpler fast exact geometric searches of potential side chain positioning include mimicking binding hotspots, design of metal binding clusters and the design of modular hydrogen binding networks for specificity. In these applications the speed and scaling of geometric search limits downstream design to small patterns. Here we present an adaptive algorithm to searching for side chain take-off angles compatible with an arbitrarily specified functional pattern that enjoys substantive performance improvements over previous methods. We demonstrate this method in both genetically encoded (protein) and synthetic (peptidomimetic) design scenarios. Examples of using this method with the Rosetta framework for protein design are provided but our implementation is compatible with multiple protein design frameworks and is freely available as a set of python scripts (https://github.com/JiangTian/adaptive-geometric-search-for-protein-design).