title: Improving predicted protein loop structure ranking using a Pareto-optimality consensus method.
abstract: BACKGROUND
  Accurate protein loop structure models are important to understand functions of many proteins. Identifying the native or near-native models by distinguishing them from the misfolded ones is a critical step in protein loop structure prediction.
  
  
  RESULTS
  We have developed a Pareto Optimal Consensus (POC) method, which is a consensus model ranking approach to integrate multiple knowledge- or physics-based scoring functions. The procedure of identifying the models of best quality in a model set includes: 1) identifying the models at the Pareto optimal front with respect to a set of scoring functions, and 2) ranking them based on the fuzzy dominance relationship to the rest of the models. We apply the POC method to a large number of decoy sets for loops of 4- to 12-residue in length using a functional space composed of several carefully-selected scoring functions: Rosetta, DOPE, DDFIRE, OPLS-AA, and a triplet backbone dihedral potential developed in our lab. Our computational results show that the sets of Pareto-optimal decoys, which are typically composed of approximately 20% or less of the overall decoys in a set, have a good coverage of the best or near-best decoys in more than 99% of the loop targets. Compared to the individual scoring function yielding best selection accuracy in the decoy sets, the POC method yields 23%, 37%, and 64% less false positives in distinguishing the native conformation, indentifying a near-native model (RMSD < 0.5A from the native) as top-ranked, and selecting at least one near-native model in the top-5-ranked models, respectively. Similar effectiveness of the POC method is also found in the decoy sets from membrane protein loops. Furthermore, the POC method outperforms the other popularly-used consensus strategies in model ranking, such as rank-by-number, rank-by-rank, rank-by-vote, and regression-based methods.
  
  
  CONCLUSIONS
  By integrating multiple knowledge- and physics-based scoring functions based on Pareto optimality and fuzzy dominance, the POC method is effective in distinguishing the best loop models from the other ones within a loop model set.
authors.affiliation: Department of Computer Science, Old Dominion University, Norfolk, VA 23529, USA. yaohang@cs.odu.edu
authors.forename: Yaohang
authors.initials: Y
authors.lastname: Li
authors.forename: Ionel
authors.initials: I
authors.lastname: Rata
authors.forename: See-wing
authors.initials: SW
authors.lastname: Chiu
authors.forename: Eric
authors.initials: E
authors.lastname: Jakobsson
mesh_terms: D019295:Computational Biology / Q000379:methods*; D008958:Models, Molecular; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D012372:ROC Curve
chemical_list: D011506:Proteins