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1.  Protein threading using context-specific alignment potential 
Bioinformatics  2013;29(13):i257-i265.
Motivation: Template-based modeling, including homology modeling and protein threading, is the most reliable method for protein 3D structure prediction. However, alignment errors and template selection are still the main bottleneck for current template-base modeling methods, especially when proteins under consideration are distantly related.
Results: We present a novel context-specific alignment potential for protein threading, including alignment and template selection. Our alignment potential measures the log-odds ratio of one alignment being generated from two related proteins to being generated from two unrelated proteins, by integrating both local and global context-specific information. The local alignment potential quantifies how well one sequence residue can be aligned to one template residue based on context-specific information of the residues. The global alignment potential quantifies how well two sequence residues can be placed into two template positions at a given distance, again based on context-specific information. By accounting for correlation among a variety of protein features and making use of context-specific information, our alignment potential is much more sensitive than the widely used context-independent or profile-based scoring function. Experimental results confirm that our method generates significantly better alignments and threading results than the best profile-based methods on several large benchmarks. Our method works particularly well for distantly related proteins or proteins with sparse sequence profiles because of the effective integration of context-specific, structure and global information.
Availability: http://raptorx.uchicago.edu/download/.
Contact: jinboxu@gmail.com
doi:10.1093/bioinformatics/btt210
PMCID: PMC3694651  PMID: 23812991
2.  Alignment of distantly related protein structures: algorithm, bound and implications to homology modeling 
Bioinformatics  2011;27(18):2537-2545.
Motivation: Building an accurate alignment of a large set of distantly related protein structures is still very challenging.
Results: This article presents a novel method 3DCOMB that can generate a multiple structure alignment (MSA) with not only as many conserved cores as possible, but also high-quality pairwise alignments. 3DCOMB is unique in that it makes use of both local and global structure environments, combined by a statistical learning method, to accurately identify highly similar fragment blocks (HSFBs) among all proteins to be aligned. By extending the alignments of these HSFBs, 3DCOMB can quickly generate an accurate MSA without using progressive alignment. 3DCOMB significantly excels others in aligning distantly related proteins. 3DCOMB can also generate correct alignments for functionally similar regions among proteins of very different structures while many other MSA tools fail. 3DCOMB is useful for many real-world applications. In particular, it enables us to find out that there is still large improvement room for multiple template homology modeling while several other MSA tools fail to do so.
Availability: 3DCOMB is available at http://ttic.uchicago.edu/~jinbo/software.htm.
Contact: jinboxu@gmail.com
Supplementary Information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btr432
PMCID: PMC3167051  PMID: 21791532
3.  A conditional neural fields model for protein threading 
Bioinformatics  2012;28(12):i59-i66.
Motivation: Alignment errors are still the main bottleneck for current template-based protein modeling (TM) methods, including protein threading and homology modeling, especially when the sequence identity between two proteins under consideration is low (<30%).
Results: We present a novel protein threading method, CNFpred, which achieves much more accurate sequence–template alignment by employing a probabilistic graphical model called a Conditional Neural Field (CNF), which aligns one protein sequence to its remote template using a non-linear scoring function. This scoring function accounts for correlation among a variety of protein sequence and structure features, makes use of information in the neighborhood of two residues to be aligned, and is thus much more sensitive than the widely used linear or profile-based scoring function. To train this CNF threading model, we employ a novel quality-sensitive method, instead of the standard maximum-likelihood method, to maximize directly the expected quality of the training set. Experimental results show that CNFpred generates significantly better alignments than the best profile-based and threading methods on several public (but small) benchmarks as well as our own large dataset. CNFpred outperforms others regardless of the lengths or classes of proteins, and works particularly well for proteins with sparse sequence profiles due to the effective utilization of structure information. Our methodology can also be adapted to protein sequence alignment.
Contact: j3xu@ttic.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/bts213
PMCID: PMC3371845  PMID: 22689779

Results 1-3 (3)