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CLePAPS: Fast Pair Alignment of Protein Structures Based on Conformational Letters  [PDF]
Sheng Wang,Wei-Mou Zheng
Quantitative Biology , 2007,
Abstract: Fast, efficient and reliable algorithms for pairwise alignment of protein structures are in ever increasing demand for analyzing the rapidly growing data of protein structures. CLePAPS is a tool developed for this purpose. It distinguishes itself from other existing algorithms by the use of conformational letters, which are discretized states of 3D segmental structural states. A letter corresponds to a cluster of combinations of the three angles formed by C_alpha pseudobonds of four contiguous residues. A substitution matrix called CLESUM is available to measure similarity between any two such letters. CLePAPS regards an aligned fragment pair (AFP) as an ungapped string pair with a high sum of pairwise CLESUM scores. Using CLESUM scores as the similarity measure, CLePAPS searches for AFPs by simple string comparison. The transformation which best superimposes a highly similar AFP can be used to superimpose the structure pairs under comparison. A highly scored AFP which is consistent with several other AFPs determines an initial alignment. CLePAPS then joins consistent AFPs guided by their similarity scores to extend the alignment by several `zoom-in' iteration steps. A follow-up refinement produces the final alignment. CLePAPS does not implement dynamic programming. The utility of CLePAPS is tested on various protein structure pairs.
Hydropathy Conformational Letter and its Substitution Matrix HP-CLESUM: an Application to Protein Structural Alignment  [PDF]
Sheng Wang
Quantitative Biology , 2010,
Abstract: Motivation: Protein sequence world is discrete as 20 amino acids (AA) while its structure world is continuous, though can be discretized into structural alphabets (SA). In order to reveal the relationship between sequence and structure, it is interesting to consider both AA and SA in a joint space. However, such space has too many parameters, so the reduction of AA is necessary to bring down the parameter numbers. Result: We've developed a simple but effective approach called entropic clustering based on selecting the best mutual information between a given reduction of AAs and SAs. The optimized reduction of AA into two groups leads to hydrophobic and hydrophilic. Combined with our SA, namely conformational letter (CL) of 17 alphabets, we get a joint alphabet called hydropathy conformational letter (hp-CL). A joint substitution matrix with (17*2)*(17*2) indices is derived from FSSP. Moreover, we check the three coding systems, say AA, CL and hp-CL against a large database consisting proteins from family to fold, with their performance on the TopK accuracy of both similar fragment pair (SFP) and the neighbor of aligned fragment pair (AFP). The TopK selection is according to the score calculated by the coding system's substitution matrix. Finally, embedding hp-CL in a pairwise alignment algorithm, say CLeFAPS, to replace the original CL, will get an improvement on the HOMSTRAD benchmark.
FlexSnap: Flexible Non-sequential Protein Structure Alignment
Saeed Salem, Mohammed J Zaki, Chris Bystroff
Algorithms for Molecular Biology , 2010, DOI: 10.1186/1748-7188-5-12
Abstract: The effectiveness of FlexSnap is demonstrated by measuring the agreement of its alignments with manually curated non-sequential structural alignments. FlexSnap showed competitive results against state-of-the-art algorithms, like DALI, SARF2, MultiProt, FlexProt, and FATCAT. Moreover on the DynDom dataset, FlexSnap reported longer alignments with smaller rmsd.We have introduced FlexSnap, a greedy chaining algorithm that reports both sequential and non-sequential alignments and allows twists (hinges). We assessed the quality of the FlexSnap alignments by measuring its agreements with manually curated non-sequential alignments. On the FlexProt dataset, FlexSnap was competitive to state-of-the-art flexible alignment methods. Moreover, we demonstrated the benefits of introducing hinges by showing significant improvements in the alignments reported by FlexSnap for the structure pairs for which rigid alignment methods reported alignments with either low coverage or large rmsd.An implementation of the FlexSnap algorithm will be made available online at http://www.cs.rpi.edu/~zaki/software/flexsnap webcite.The wide spectrum of functions performed by proteins are enabled by their intrinsic flexibility [1]. It is known that proteins go through conformational changes to perform their functions. Homologous proteins have evolved to adopt conformational changes in their structure. Therefore, similarity between two proteins which have similar structures with one of them having undergone a conformational change will not be captured unless flexibility is considered.The problem of flexible protein structural alignment has not received much attention. Even though there are a plethora of methods for protein structure comparison [2-8], the majority of the existing methods report only sequential alignments and thus cannot capture non-sequential alignments. Non-sequential similarity can occur naturally due to circular permutations [9] or convergent evolution [10]. The case is even harder f
Nano-Scale Alignment of Proteins on a Flexible DNA Backbone  [PDF]
Tatsuya Nojima, Hiroki Konno, Noriyuki Kodera, Kohji Seio, Hideki Taguchi, Masasuke Yoshida
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0052534
Abstract: Nano-scale alignment of several proteins with freedom of motion is equivalent to an enormous increase in effective local concentration of proteins and will enable otherwise impossible weak and/or cooperative associations between them or with their ligands. For this purpose, a DNA backbone made of six oligodeoxynucleotide (ODN) chains is designed in which five double-stranded segments are connected by four single-stranded flexible linkers. A desired protein with an introduced cysteine is connected covalently to the 5′-end of azido-ODN by catalyst-free click chemistry. Then, six protein-ODN conjugates are assembled with their complementary nucleotide sequences into a single multi-protein-DNA complex, and six proteins are aligned along the DNA backbone. Flexible alignment of proteins is directly observed by high-speed AFM imaging, and association of proteins with weak interaction is demonstrated by fluorescence resonance energy transfer between aligned proteins.
A Conformational Study of Flexible Cyclic Compounds (Hydrocarbon Rings of 9-12 Members)  [PDF]
F. Suvire,S. Rodríguez,L. Santagata,A. Rodríguez,R. Enriz
Molecules , 2000, DOI: 10.3390/50300585
Abstract: We report here a conformational study of cyclic flexible compounds (rings with 9-12 members). Two methods of systematic search for the minima were used. The results were compared with those obtained using other exploratory methods.
Alignment of protein structures in the presence of domain motions
Roberto Mosca, Barbara Brannetti, Thomas R Schneider
BMC Bioinformatics , 2008, DOI: 10.1186/1471-2105-9-352
Abstract: We introduce a new method called RAPIDO (Rapid Alignment of Proteins in terms of Domains) for the three-dimensional alignment of protein structures in the presence of conformational changes. The flexible aligner is coupled to a genetic algorithm for the identification of structurally conserved regions. RAPIDO is capable of aligning protein structures in the presence of large conformational changes. Structurally conserved regions are reliably detected even if they are discontinuous in sequence but continuous in space and can be used for superpositions revealing subtle differences.RAPIDO is more sensitive than other flexible aligners when applied to cases of closely homologues proteins undergoing large conformational changes. When applied to a set of kinase structures it is able to detect similarities that are missed by other alignment algorithms. The algorithm is sufficiently fast to be applied to the comparison of large sets of protein structures.When comparing structures of related proteins with different amino-acid sequences it is necessary to first perform a structural alignment, i.e. to define an equivalence map between the residues in the different structures based on their relative position in space. Once structures have been successfully aligned in three dimensions, similarities and differences can be studied in order to understand function and behaviour of the molecules under consideration.It has been demonstrated that the problem of defining an equivalence map for residues in protein structures has no unique optimal solution [1] and that it remains computationally hard [2-4] even when it is described by a well defined optimization function. Nevertheless, many tools have been created for the pairwise and the multiple alignment of protein structures using different heuristics to produce results on acceptable time-scales (for comprehensive reviews see [5-7]).Alignment methods can be classified based on whether the two structures to be aligned are considered as
β-Lactoglobulin's Conformational Requirements for Ligand Binding at the Calyx and the Dimer Interphase: a Flexible Docking Study  [PDF]
Lenin Domínguez-Ramírez, Elizabeth Del Moral-Ramírez, Paulina Cortes-Hernández, Mariano García-Garibay, Judith Jiménez-Guzmán
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0079530
Abstract: β-lactoglobulin (BLG) is an abundant milk protein relevant for industry and biotechnology, due significantly to its ability to bind a wide range of polar and apolar ligands. While hydrophobic ligand sites are known, sites for hydrophilic ligands such as the prevalent milk sugar, lactose, remain undetermined. Through the use of molecular docking we first, analyzed the known fatty acid binding sites in order to dissect their atomistic determinants and second, predicted the interaction sites for lactose with monomeric and dimeric BLG. We validated our approach against BLG structures co-crystallized with ligands and report a computational setup with a reduced number of flexible residues that is able to reproduce experimental results with high precision. Blind dockings with and without flexible side chains on BLG showed that: i) 13 experimentally-determined ligands fit the calyx requiring minimal movement of up to 7 residues out of the 23 that constitute this binding site. ii) Lactose does not bind the calyx despite conformational flexibility, but binds the dimer interface and an alternate Site C. iii) Results point to a probable lactolation site in the BLG dimer interface, at K141, consistent with previous biochemical findings. In contrast, no accessible lysines are found near Site C. iv) lactose forms hydrogen bonds with residues from both monomers stabilizing the dimer through a claw-like structure. Overall, these results improve our understanding of BLG's binding sites, importantly narrowing down the calyx residues that control ligand binding. Moreover, our results emphasize the importance of the dimer interface as an insufficiently explored, biologically relevant binding site of particular importance for hydrophilic ligands. Furthermore our analyses suggest that BLG is a robust scaffold for multiple ligand-binding, suitable for protein design, and advance our molecular understanding of its ligand sites to a point that allows manipulation to control binding.
CONFORMATIONAL ANALYSIS: A REVIEW  [PDF]
Jasmine Uthuppan*1 and Kriti Soni 2
International Journal of Pharmaceutical Sciences and Research , 2013,
Abstract: Conformational analysis is an important step in molecular modeling as it is necessary to reduce time spent in screening of compounds for activity. Most drugs are flexible molecules with the ability to adopt different conformations by means of rotation about single bonds. Conformations play an important role in prediction of not just physico-chemical properties but also the biological activity of the drug. This review details the various methods involved in conformational analysis. The major objective of conformational analysis is to gain insight on conformational characteristic of drugs and also to identify the relation between the role of conformational flexibility and their activity.
4D Flexible Atom-Pairs: An efficient probabilistic conformational space comparison for ligand-based virtual screening
Andreas Jahn, Lars Rosenbaum, Georg Hinselmann, Andreas Zell
Journal of Cheminformatics , 2011, DOI: 10.1186/1758-2946-3-23
Abstract: Comparisons of our 4D flexible atom-pair approach with over 15 state-of-the-art 2D- and 3D-based virtual screening similarity functions on the 40 data sets of the Directory of Useful Decoys show a robust performance of our approach. Even 3D-based approaches that operate on multiple conformers yield inferior results. The 4D flexible atom-pair method achieves an averaged AUC value of 0.78 on the filtered Directory of Useful Decoys data sets. The best 2D- and 3D-based approaches of this study yield an AUC value of 0.74 and 0.72, respectively. As a result, the 4D flexible atom-pair approach achieves an average rank of 1.25 with respect to 15 other state-of-the-art similarity functions and four different evaluation metrics.Our 4D method yields a robust performance on 40 pharmaceutically relevant targets. The conformational space encoding enables an efficient comparison of the conformational space. Therefore, the weakness of the 3D-based approaches on single conformations is circumvented. With over 100,000 similarity calculations on a single desktop CPU, the utilization of the 4D flexible atom-pair in real-world applications is feasible.Sorting and comparing molecules from chemical databases represent two of the key tasks in cheminformatics [1]. The sorting of such databases, with respect to a given set of queries (molecules) and similarity functions, is known as virtual screening (VS). The goal of VS is to enrich molecules with similar properties (e.g., biological activity) to the query molecules and to discover new chemical entities in a small fraction of the database. To ensure the desired properties (e.g., biological activity) and to evaluate the success of the VS run, it is necessary to further analyze the enriched molecules by means of biological assays. The success of a VS run consists of two different aspects. First, the enriched molecules should have similar properties as the query molecules. Second, the discovery of new chemical entities that consist of differen
TOPS++FATCAT: Fast flexible structural alignment using constraints derived from TOPS+ Strings Model
Mallika Veeramalai, Yuzhen Ye, Adam Godzik
BMC Bioinformatics , 2008, DOI: 10.1186/1471-2105-9-358
Abstract: We developed a TOPS++FATCAT algorithm that uses an intuitive description of the proteins' structures as captured in the popular TOPS diagrams to limit the search space of the aligned fragment pairs (AFPs) in the flexible alignment of protein structures performed by the FATCAT algorithm. The TOPS++FATCAT algorithm is faster than FATCAT by more than an order of magnitude with a minimal cost in classification and alignment accuracy. For beta-rich proteins its accuracy is better than FATCAT, because the TOPS+ strings models contains important information of the parallel and anti-parallel hydrogen-bond patterns between the beta-strand SSEs (Secondary Structural Elements). We show that the TOPS++FATCAT errors, rare as they are, can be clearly linked to oversimplifications of the TOPS diagrams and can be corrected by the development of more precise secondary structure element definitions.The benchmark analysis results and the compressed archive of the TOPS++FATCAT program for Linux platform can be downloaded from the following web site: http://fatcat.burnham.org/TOPS/ webciteTOPS++FATCAT provides FATCAT accuracy and insights into protein structural changes at a speed comparable to sequence alignments, opening up a possibility of interactive protein structure similarity searches.Structural biology is one of the most successful fields of modern biology. Over 50,000 solved protein structures illustrate details of many specific biological processes. The same data also provide us with information about the global features of protein structure space and can be studied to discover the evolutionary, physical, and mathematical rules governing them. How many fundamentally different protein shapes (folds) are there? How do protein structures evolve? How do new structural features appear, and if they are coupled with changes in function, how does this process occur? Such questions can be studied by classifying, comparing and analyzing known protein structures. Two different, but syner
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