A Pareto-optimal refinement method for protein design scaffolds

PLoS One. 2013;8(4):e59004. doi: 10.1371/journal.pone.0059004. Epub 2013 Apr 2.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Algorithms*
  • Amino Acids / chemistry
  • Binding Sites
  • Computer Simulation
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Proteins / chemistry*
  • Proteins / metabolism

Substances

  • Amino Acids
  • Proteins

Grant support

DB and RM were supported by a Defense Advanced Research Projects Agency/Defense Threat Reduction Agency grant, Protein Design Processes. LGN was supported by a National Science Foundation Minority Postdoctoral Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.