MUFOLD-WQA: A new selective consensus method for quality assessment in protein structure prediction.

Assessing the quality of predicted models is essential in protein tertiary structure prediction. In the past critical assessment of techniques for protein structure prediction (CASP) experiments, consensus quality assessment (QA) methods have shown to be very effective, outperforming single-model methods and other competing approaches by a large margin. In the consensus QA approach, the quality score of a model is typically estimated based on pair-wise structure similarity of it to a set of reference models. In CASP8, the differences among the top QA servers were mostly in the selection of the reference models. In this article, we present a new consensus method "SelCon" based on two key ideas: (1) to adaptively select appropriate reference models based on the attributes of the whole set of predicted models and (2) to weigh different reference models differently, and in particular not to use models that are too similar or too different from the candidate model as its references. We have developed several reference selection functions in SelCon and obtained improved QA results over existing QA methods in experiments using CASP7 and CASP8 data. In the recently completed CASP9 in 2010, the new method was implemented in our MUFOLD-WQA server. Both the official CASP9 assessment and our in-house evaluation showed that MUFOLD-WQA performed very well and achieved top performances in both the global structure QA and top-model selection category in CASP9.

A multilayer evaluation approach for protein structure prediction and model quality assessment.

Protein tertiary structures are essential for studying functions of proteins at molecular level. An indispensable approach for protein structure solution is computational prediction. Most protein structure prediction methods generate candidate models first and select the best candidates by model quality assessment (QA). In many cases, good models can be produced, but the QA tools fail to select the best ones from the candidate model pool. Because of incomplete understanding of protein folding, each QA method only reflects partial facets of a structure model and thus has limited discerning power with no one consistently outperforming others. In this article, we developed a set of new QA methods, including two QA methods for evaluating target/template alignments, a molecular dynamics (MD)-based QA method, and three consensus QA methods with selected references to reveal new facets of protein structures complementary to the existing methods. Moreover, the underlying relationship among different QA methods were analyzed and then integrated into a multilayer evaluation approach to guide the model generation and model selection in prediction. All methods are integrated and implemented into an innovative and improved prediction system hereafter referred to as MUFOLD. In CASP8 and CASP9, MUFOLD has demonstrated the proof of the principles in terms of both QA discerning power and structure prediction accuracy.