Abstract
BackgroundAccurate 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.ResultsWe 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 ~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.ConclusionsBy 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.
Highlights
Accurate protein loop structure models are important to understand functions of many proteins
We present a Pareto Optimality Consensus (POC) method based on the Pareto optimality [43] and fuzzy dominance theory [44] to take advantage of multiple scoring functions for ranking protein loop models
Efficiency in Identifying Near-Native Structures We applied the POC method to the decoy sets generated by Jacobson et al The decoy set for each target contains very good models (MODEL 1 and MODEL 2) derived from the native structure by optimizing the OPLS-AA/ SGB force field as well as other models generated by hierarchical comparative modeling [6]
Summary
Accurate protein loop structure models are important to understand functions of many proteins. Xiang et al [10] developed a combined energy function with force-field energy and RMSD (Root Mean Square Deviation) dependent terms. They developed the concept of "colony energy" that has been used by Fogolari and Tosatto [16] as well, for considering the loop entropy (an important component in flexible loops) as part of the total free energy. DFIRE has previously proven to be successful by itself for loop selection [21] All these methods have led to recent significant progress in generating high-resolution loop models and several loop prediction servers are available (see [22], for example)
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