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Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
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A computational method for the design of nested proteins by loop-directed domain insertion.

Kristin M Blacklock1,2,3, Lu Yang2,3, Vikram K Mulligan4

  • 1Institute for Quantitative Biomedicine, Rutgers The State University of New Jersey, Piscataway, New Jersey.

Proteins
|December 19, 2017
PubMed
Summary

A new computational method, Loop-Directed Domain Insertion (LooDo), designs novel nested proteins by combining protein domains. This approach enables the creation of multifunctional proteins with potential applications in protein engineering.

Keywords:
Rosetta modelingdomain insertionenzyme designkinematic loop closuremulti-domain proteinnested proteinprotein designα/β hydrolase

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Area of Science:

  • Computational protein design
  • Protein engineering
  • Bioinformatics

Background:

  • Designing multifunctional proteins requires novel approaches to combine protein domains.
  • Nested protein structures, where one domain is inserted within another, offer a route to creating complex protein architectures.

Purpose of the Study:

  • To present a new algorithm, Loop-Directed Domain Insertion (LooDo), for designing nested protein domain combinations.
  • To enable the computational generation of multifunctional proteins by connecting domains with flexible linkers.

Main Methods:

  • Developed the LooDo algorithm within the Rosetta software suite.
  • Employed linker fragment libraries for conformational sampling and grid-based searches for domain superimposition.
  • Utilized kinematic loop closure and Rosetta EnzymeDesign for optimizing loop and interface residues.

Main Results:

  • LooDo successfully sampled near-native conformations and interface sequences for benchmark α/β hydrolase superfamily enzymes.
  • The algorithm demonstrated discrimination between native and non-native protein conformations and sequences.
  • Native insert-parent domain combinations were consistently ranked higher than non-native combinations.

Conclusions:

  • The LooDo algorithm is effective for designing nested protein domain combinations.
  • This method holds broad applicability for creating multi-domain protein complexes with inserted or tandem domain connections.
  • The approach facilitates the generation of novel multifunctional proteins.