An adaptive geometric search algorithm for macromolecular scaffold selection

Tian Jiang, P. Douglas Renfrew, Kevin Drew, Noah Youngs, Glenn Butterfoss, Richard Bonneau, Dennis Shasha

Research output: Contribution to journalArticle

Abstract

A wide variety of protein and peptidomimetic design tasks require matching functional 3D motifs to potential oligomeric scaffolds. For example, during enzyme design, one aims to graft active-site patterns-typically consisting of 3-15 residues-onto new protein surfaces. Identifying protein scaffolds suitable for such active-site engraftment requires costly searches for protein folds that provide the correct side chain positioning to host the desired active site. Other examples of biodesign tasks that require similar 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 searches limits the scope of downstream design to small patterns. Here, we present an adaptive algorithm capable of searching for side chain take-off angles, which is compatible with an arbitrarily specified functional pattern and which 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. 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).

Original languageEnglish (US)
Pages (from-to)345-354
Number of pages10
JournalProtein engineering, design & selection : PEDS
Volume31
Issue number9
DOIs
StatePublished - Sep 1 2018

Fingerprint

Scaffolds (biology)
Scaffolds
Proteins
Peptidomimetics
Catalytic Domain
Boidae
Hydrogen
Takeoff
Membrane Proteins
Adaptive algorithms
Metals
Grafts
Transplants
Enzymes

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biochemistry
  • Molecular Biology

Cite this

An adaptive geometric search algorithm for macromolecular scaffold selection. / Jiang, Tian; Renfrew, P. Douglas; Drew, Kevin; Youngs, Noah; Butterfoss, Glenn; Bonneau, Richard; Shasha, Dennis.

In: Protein engineering, design & selection : PEDS, Vol. 31, No. 9, 01.09.2018, p. 345-354.

Research output: Contribution to journalArticle

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