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1.  Optimizing a global alignment of protein interaction networks 
Bioinformatics  2013;29(21):2765-2773.
Motivation: The global alignment of protein interaction networks is a widely studied problem. It is an important first step in understanding the relationship between the proteins in different species and identifying functional orthologs. Furthermore, it can provide useful insights into the species’ evolution.
Results: We propose a novel algorithm, PISwap, for optimizing global pairwise alignments of protein interaction networks, based on a local optimization heuristic that has previously demonstrated its effectiveness for a variety of other intractable problems. PISwap can begin with different types of network alignment approaches and then iteratively adjust the initial alignments by incorporating network topology information, trading it off for sequence information. In practice, our algorithm efficiently refines other well-studied alignment techniques with almost no additional time cost. We also show the robustness of the algorithm to noise in protein interaction data. In addition, the flexible nature of this algorithm makes it suitable for different applications of network alignment. This algorithm can yield interesting insights into the evolutionary dynamics of related species.
Availability: Our software is freely available for non-commercial purposes from our Web site, http://piswap.csail.mit.edu/.
Contact: bab@csail.mit.edu or csliao@ie.nthu.edu.tw
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt486
PMCID: PMC3799479  PMID: 24048352
2.  Compressive genomics for protein databases 
Bioinformatics  2013;29(13):i283-i290.
Motivation: The exponential growth of protein sequence databases has increasingly made the fundamental question of searching for homologs a computational bottleneck. The amount of unique data, however, is not growing nearly as fast; we can exploit this fact to greatly accelerate homology search. Acceleration of programs in the popular PSI/DELTA-BLAST family of tools will not only speed-up homology search directly but also the huge collection of other current programs that primarily interact with large protein databases via precisely these tools.
Results: We introduce a suite of homology search tools, powered by compressively accelerated protein BLAST (CaBLASTP), which are significantly faster than and comparably accurate with all known state-of-the-art tools, including HHblits, DELTA-BLAST and PSI-BLAST. Further, our tools are implemented in a manner that allows direct substitution into existing analysis pipelines. The key idea is that we introduce a local similarity-based compression scheme that allows us to operate directly on the compressed data. Importantly, CaBLASTP’s runtime scales almost linearly in the amount of unique data, as opposed to current BLASTP variants, which scale linearly in the size of the full protein database being searched. Our compressive algorithms will speed-up many tasks, such as protein structure prediction and orthology mapping, which rely heavily on homology search.
Availability: CaBLASTP is available under the GNU Public License at http://cablastp.csail.mit.edu/
Contact: bab@mit.edu
doi:10.1093/bioinformatics/btt214
PMCID: PMC3851851  PMID: 23812995
3.  Editorial 
Bioinformatics  2012;28(12):i1.
doi:10.1093/bioinformatics/bts281
PMCID: PMC3371872  PMID: 22689748
4.  SMURFLite: combining simplified Markov random fields with simulated evolution improves remote homology detection for beta-structural proteins into the twilight zone 
Bioinformatics  2012;28(9):1216-1222.
Motivation: One of the most successful methods to date for recognizing protein sequences that are evolutionarily related has been profile hidden Markov models (HMMs). However, these models do not capture pairwise statistical preferences of residues that are hydrogen bonded in beta sheets. These dependencies have been partially captured in the HMM setting by simulated evolution in the training phase and can be fully captured by Markov random fields (MRFs). However, the MRFs can be computationally prohibitive when beta strands are interleaved in complex topologies. We introduce SMURFLite, a method that combines both simplified MRFs and simulated evolution to substantially improve remote homology detection for beta structures. Unlike previous MRF-based methods, SMURFLite is computationally feasible on any beta-structural motif.
Results: We test SMURFLite on all propeller and barrel folds in the mainly-beta class of the SCOP hierarchy in stringent cross-validation experiments. We show a mean 26% (median 16%) improvement in area under curve (AUC) for beta-structural motif recognition as compared with HMMER (a well-known HMM method) and a mean 33% (median 19%) improvement as compared with RAPTOR (a well-known threading method) and even a mean 18% (median 10%) improvement in AUC over HHPred (a profile–profile HMM method), despite HHpred's use of extensive additional training data. We demonstrate SMURFLite's ability to scale to whole genomes by running a SMURFLite library of 207 beta-structural SCOP superfamilies against the entire genome of Thermotoga maritima, and make over a 100 new fold predictions.
Availability and implementaion: A webserver that runs SMURFLite is available at: http://smurf.cs.tufts.edu/smurflite/
Contact: lenore.cowen@tufts.edu; bab@mit.edu
doi:10.1093/bioinformatics/bts110
PMCID: PMC3338012  PMID: 22408192
5.  A method for probing the mutational landscape of amyloid structure 
Bioinformatics  2011;27(13):i34-i42.
Motivation: Proteins of all kinds can self-assemble into highly ordered β-sheet aggregates known as amyloid fibrils, important both biologically and clinically. However, the specific molecular structure of a fibril can vary dramatically depending on sequence and environmental conditions, and mutations can drastically alter amyloid function and pathogenicity. Experimental structure determination has proven extremely difficult with only a handful of NMR-based models proposed, suggesting a need for computational methods.
Results: We present AmyloidMutants, a statistical mechanics approach for de novo prediction and analysis of wild-type and mutant amyloid structures. Based on the premise of protein mutational landscapes, AmyloidMutants energetically quantifies the effects of sequence mutation on fibril conformation and stability. Tested on non-mutant, full-length amyloid structures with known chemical shift data, AmyloidMutants offers roughly 2-fold improvement in prediction accuracy over existing tools. Moreover, AmyloidMutants is the only method to predict complete super-secondary structures, enabling accurate discrimination of topologically dissimilar amyloid conformations that correspond to the same sequence locations. Applied to mutant prediction, AmyloidMutants identifies a global conformational switch between Aβ and its highly-toxic ‘Iowa’ mutant in agreement with a recent experimental model based on partial chemical shift data. Predictions on mutant, yeast-toxic strains of HET-s suggest similar alternate folds. When applied to HET-s and a HET-s mutant with core asparagines replaced by glutamines (both highly amyloidogenic chemically similar residues abundant in many amyloids), AmyloidMutants surprisingly predicts a greatly reduced capacity of the glutamine mutant to form amyloid. We confirm this finding by conducting mutagenesis experiments.
Availability: Our tool is publically available on the web at http://amyloid.csail.mit.edu/.
Contact: lindquist_admin@wi.mit.edu; bab@csail.mit.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btr238
PMCID: PMC3117379  PMID: 21685090
6.  IsoRankN: spectral methods for global alignment of multiple protein networks 
Bioinformatics  2009;25(12):i253-i258.
Motivation: With the increasing availability of large protein–protein interaction networks, the question of protein network alignment is becoming central to systems biology. Network alignment is further delineated into two sub-problems: local alignment, to find small conserved motifs across networks, and global alignment, which attempts to find a best mapping between all nodes of the two networks. In this article, our aim is to improve upon existing global alignment results. Better network alignment will enable, among other things, more accurate identification of functional orthologs across species.
Results: We introduce IsoRankN (IsoRank-Nibble) a global multiple-network alignment tool based on spectral clustering on the induced graph of pairwise alignment scores. IsoRankN outperforms existing algorithms for global network alignment in coverage and consistency on multiple alignments of the five available eukaryotic networks. Being based on spectral methods, IsoRankN is both error tolerant and computationally efficient.
Availability: Our software is available freely for non-commercial purposes on request from: http://isorank.csail.mit.edu/
Contact: bab@mit.edu
doi:10.1093/bioinformatics/btp203
PMCID: PMC2687957  PMID: 19477996
7.  Optimal contact map alignment of protein–protein interfaces 
Bioinformatics  2008;24(20):2324-2328.
The long-standing problem of constructing protein structure alignments is of central importance in computational biology. The main goal is to provide an alignment of residue correspondences, in order to identify homologous residues across chains. A critical next step of this is the alignment of protein complexes and their interfaces. Here, we introduce the program CMAPi, a two-dimensional dynamic programming algorithm that, given a pair of protein complexes, optimally aligns the contact maps of their interfaces: it produces polynomial-time near-optimal alignments in the case of multiple complexes. We demonstrate the efficacy of our algorithm on complexes from PPI families listed in the SCOPPI database and from highly divergent cytokine families. In comparison to existing techniques, CMAPi generates more accurate alignments of interacting residues within families of interacting proteins, especially for sequences with low similarity. While previous methods that use an all-atom based representation of the interface have been successful, CMAPi's use of a contact map representation allows it to be more tolerant to conformational changes and thus to align more of the interaction surface. These improved interface alignments should enhance homology modeling and threading methods for predicting PPIs by providing a basis for generating template profiles for sequence–structure alignment.
Contact: bab@mit.edu; jbienkowska@gmail.com
Supplementary information: Supplementary data are available at http://theory.csail.mit.edu/cmapi
doi:10.1093/bioinformatics/btn432
PMCID: PMC2562013  PMID: 18710876

Results 1-7 (7)