A Pareto-Optimal Refinement Method for Protein Design Scaffolds

Computational design of protein function involves a search for amino acids with the lowest energy subject to a set of constraints specifying function. In many cases a set of natural protein backbone structures, or "scaffolds", are searched to find regions where functional sites (an enzyme...

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Published inPloS one Vol. 8; no. 4; p. e59004
Main Authors Nivón, Lucas Gregorio, Moretti, Rocco, Baker, David
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 02.04.2013
Public Library of Science (PLoS)
Subjects
Algorithms
Amino acids
Amino Acids - chemistry
Backbone
Binding Sites
Biochemistry
Biology
Computational biology
Computer applications
Computer Simulation
Design
Energy
Enzymes
Ligands
Methods
Molecular biology
Mutation
Optimization
Packaging
Pareto optimum
Protein Conformation
Protein Interaction Domains and Motifs
Proteins
Proteins - chemistry
Proteins - metabolism
Protocol
Scaffolds
Structure
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Summary:Computational design of protein function involves a search for amino acids with the lowest energy subject to a set of constraints specifying function. In many cases a set of natural protein backbone structures, or "scaffolds", are searched to find regions where functional sites (an enzyme active site, ligand binding pocket, protein-protein interaction region, etc.) can be placed, and the identities of the surrounding amino acids are optimized to satisfy functional constraints. Input native protein structures almost invariably have regions that score very poorly with the design force field, and any design based on these unmodified structures may result in mutations away from the native sequence solely as a result of the energetic strain. Because the input structure is already a stable protein, it is desirable to keep the total number of mutations to a minimum and to avoid mutations resulting from poorly-scoring input structures. Here we describe a protocol using cycles of minimization with combined backbone/sidechain restraints that is Pareto-optimal with respect to RMSD to the native structure and energetic strain reduction. The protocol should be broadly useful in the preparation of scaffold libraries for functional site design.
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Competing Interests: The authors have declared that no competing interests exist.
Conceived and designed the experiments: LGN RM DB. Performed the experiments: LGN RM. Analyzed the data: LGN RM. Contributed reagents/materials/analysis tools: LGN RM. Wrote the paper: LGN RM DB.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0059004