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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.  Predicting protein contact map using evolutionary and physical constraints by integer programming 
Bioinformatics  2013;29(13):i266-i273.
Motivation: Protein contact map describes the pairwise spatial and functional relationship of residues in a protein and contains key information for protein 3D structure prediction. Although studied extensively, it remains challenging to predict contact map using only sequence information. Most existing methods predict the contact map matrix element-by-element, ignoring correlation among contacts and physical feasibility of the whole-contact map. A couple of recent methods predict contact map by using mutual information, taking into consideration contact correlation and enforcing a sparsity restraint, but these methods demand for a very large number of sequence homologs for the protein under consideration and the resultant contact map may be still physically infeasible.
Results: This article presents a novel method PhyCMAP for contact map prediction, integrating both evolutionary and physical restraints by machine learning and integer linear programming. The evolutionary restraints are much more informative than mutual information, and the physical restraints specify more concrete relationship among contacts than the sparsity restraint. As such, our method greatly reduces the solution space of the contact map matrix and, thus, significantly improves prediction accuracy. Experimental results confirm that PhyCMAP outperforms currently popular methods no matter how many sequence homologs are available for the protein under consideration.
Availability: http://raptorx.uchicago.edu.
Contact: jinboxu@gmail.com
doi:10.1093/bioinformatics/btt211
PMCID: PMC3694661  PMID: 23812992
3.  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
4.  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
5.  A conditional random fields method for RNA sequence–structure relationship modeling and conformation sampling 
Bioinformatics  2011;27(13):i102-i110.
Accurate tertiary structures are very important for the functional study of non-coding RNA molecules. However, predicting RNA tertiary structures is extremely challenging, because of a large conformation space to be explored and lack of an accurate scoring function differentiating the native structure from decoys. The fragment-based conformation sampling method (e.g. FARNA) bears shortcomings that the limited size of a fragment library makes it infeasible to represent all possible conformations well. A recent dynamic Bayesian network method, BARNACLE, overcomes the issue of fragment assembly. In addition, neither of these methods makes use of sequence information in sampling conformations. Here, we present a new probabilistic graphical model, conditional random fields (CRFs), to model RNA sequence–structure relationship, which enables us to accurately estimate the probability of an RNA conformation from sequence. Coupled with a novel tree-guided sampling scheme, our CRF model is then applied to RNA conformation sampling. Experimental results show that our CRF method can model RNA sequence–structure relationship well and sequence information is important for conformation sampling. Our method, named as TreeFolder, generates a much higher percentage of native-like decoys than FARNA and BARNACLE, although we use the same simple energy function as BARNACLE.
Contact: zywang@ttic.edu; j3xu@ttic.edu
Supplementary Information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btr232
PMCID: PMC3117333  PMID: 21685058
6.  Low-homology protein threading 
Bioinformatics  2010;26(12):i294-i300.
Motivation: The challenge of template-based modeling lies in the recognition of correct templates and generation of accurate sequence-template alignments. Homologous information has proved to be very powerful in detecting remote homologs, as demonstrated by the state-of-the-art profile-based method HHpred. However, HHpred does not fare well when proteins under consideration are low-homology. A protein is low-homology if we cannot obtain sufficient amount of homologous information for it from existing protein sequence databases.
Results: We present a profile-entropy dependent scoring function for low-homology protein threading. This method will model correlation among various protein features and determine their relative importance according to the amount of homologous information available. When proteins under consideration are low-homology, our method will rely more on structure information; otherwise, homologous information. Experimental results indicate that our threading method greatly outperforms the best profile-based method HHpred and all the top CASP8 servers on low-homology proteins. Tested on the CASP8 hard targets, our threading method is also better than all the top CASP8 servers but slightly worse than Zhang-Server. This is significant considering that Zhang-Server and other top CASP8 servers use a combination of multiple structure-prediction techniques including consensus method, multiple-template modeling, template-free modeling and model refinement while our method is a classical single-template-based threading method without any post-threading refinement.
Contact: jinboxu@gmail.com
doi:10.1093/bioinformatics/btq192
PMCID: PMC2881377  PMID: 20529920
7.  Fragment-free approach to protein folding using conditional neural fields 
Bioinformatics  2010;26(12):i310-i317.
Motivation: One of the major bottlenecks with ab initio protein folding is an effective conformation sampling algorithm that can generate native-like conformations quickly. The popular fragment assembly method generates conformations by restricting the local conformations of a protein to short structural fragments in the PDB. This method may limit conformations to a subspace to which the native fold does not belong because (i) a protein with really new fold may contain some structural fragments not in the PDB and (ii) the discrete nature of fragments may prevent them from building a native-like fold. Previously we have developed a conditional random fields (CRF) method for fragment-free protein folding that can sample conformations in a continuous space and demonstrated that this CRF method compares favorably to the popular fragment assembly method. However, the CRF method is still limited by its capability of generating conformations compatible with a sequence.
Results: We present a new fragment-free approach to protein folding using a recently invented probabilistic graphical model conditional neural fields (CNF). This new CNF method is much more powerful than CRF in modeling the sophisticated protein sequence-structure relationship and thus, enables us to generate native-like conformations more easily. We show that when coupled with a simple energy function and replica exchange Monte Carlo simulation, our CNF method can generate decoys much better than CRF on a variety of test proteins including the CASP8 free-modeling targets. In particular, our CNF method can predict a correct fold for T0496_D1, one of the two CASP8 targets with truly new fold. Our predicted model for T0496 is significantly better than all the CASP8 models.
Contact: jinboxu@gmail.com
doi:10.1093/bioinformatics/btq193
PMCID: PMC2881378  PMID: 20529922
8.  Designing succinct structural alphabets 
Bioinformatics  2008;24(13):i182-i189.
Motivation: The 3D structure of a protein sequence can be assembled from the substructures corresponding to small segments of this sequence. For each small sequence segment, there are only a few more likely substructures. We call them the ‘structural alphabet’ for this segment. Classical approaches such as ROSETTA used sequence profile and secondary structure information, to predict structural fragments. In contrast, we utilize more structural information, such as solvent accessibility and contact capacity, for finding structural fragments.
Results: Integer linear programming technique is applied to derive the best combination of these sequence and structural information items. This approach generates significantly more accurate and succinct structural alphabets with more than 50% improvement over the previous accuracies. With these novel structural alphabets, we are able to construct more accurate protein structures than the state-of-art ab initio protein structure prediction programs such as ROSETTA. We are also able to reduce the Kolodny's library size by a factor of 8, at the same accuracy.
Availability: The online FRazor server is under construction
Contact:scli@uwaterloo.ca,mli@uwaterloo.ca, j3xu@tti-c.org
doi:10.1093/bioinformatics/btn165
PMCID: PMC2718643  PMID: 18586712

Results 1-8 (8)