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PubMed2006

Improving the accuracy of protein secondary structure prediction using structural alignment.

BACKGROUND: The accuracy of protein secondary structure prediction has steadily improved over the past 30 years. Now many secondary structure prediction methods routinely achieve an accuracy (Q3) of about 75%. We believe this accuracy could be further improved by including structure (as opposed to sequence) database comparisons as part of the prediction process. Indeed, given the large size of the Protein Data Bank (>35,000 sequences), the probability of a newly identified sequence having a structural homologue is actually quite high. RESULTS: We have developed a method that performs structure-based sequence alignments as part of the secondary structure prediction process. By mapping the structure of a known homologue (sequence ID >25%) onto the query protein's sequence, it is possible to predict at least a portion of that query protein's secondary structure. By integrating this structural alignment approach with conventional (sequence-based) secondary structure methods and then combining it with a "jury-of-experts" system to generate a consensus result, it is possible to attain very high prediction accuracy. Using a sequence-unique test set of 1644 proteins from EVA, this new method achieves an average Q3 score of 81.3%. Extensive testing indicates this is approximately 4-5% better than any other method currently available. Assessments using non sequence-unique test sets (typical of those used in proteome annotation or structural genomics) indicate that this new method can achieve a Q3 score approaching 88%. CONCLUSION: By using both sequence and structure databases and by exploiting the latest techniques in machine learning it is possible to routinely predict protein secondary structure with an accuracy well above 80%. A program and web server, called PROTEUS, that performs these secondary structure predictions is accessible at http://wishart.biology.ualberta.ca/proteus. For high throughput or batch sequence analyses, the PROTEUS programs, databases (and server) can be downloaded and run locally.

Algorithms↗
PubMed2006

Quaternary structure of carbonmonoxyhemoglobins in solution: structural changes induced by the allosteric effector inositol hexaphosphate.

We have applied the residual dipolar coupling (RDC) method to investigate the solution quaternary structures of (2)H- and (15)N-labeled human normal adult recombinant hemoglobin (rHb A) and a low-oxygen-affinity mutant recombinant hemoglobin, rHb(alpha96Val-->Trp), both in the carbonmonoxy form, in the absence and presence of an allosteric effector, inositol hexaphosphate (IHP), using a stretched polyacrylamide gel as the alignment medium. Our recent RDC results [Lukin, J. A., Kontaxis, G., Simplaceanu, V., Yuan, Y., Bax, A., and Ho, C. (2003) Proc. Natl. Acad. Sci. U.S.A. 100, 517-520] indicate that the quaternary structure of HbCO A in solution is a dynamic ensemble between two previously determined crystal structures, R (crystals grown under high-salt conditions) and R2 (crystals grown under low-salt conditions). On the basis of a comparison of the geometric coordinates of the T, R, and R2 structures, it has been suggested that the oxygenation of Hb A follows the transition pathway from T to R and then to R2, with R being the intermediate structure [Srinivasan, R., and Rose, G. D. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 11113-11117]. The results presented here suggest that IHP can shift the solution quaternary structure of HbCO A slightly toward the R structure. The solution quaternary structure of rHbCO(alpha96Val-->Trp) in the absence of IHP is similar to that of HbCO A in the presence of IHP, consistent with rHbCO(alpha96Val-->Trp) having an affinity for oxygen lower than that of Hb A. Moreover, IHP has a much stronger effect in shifting the solution quaternary structure of rHbCO(alpha96Val-->Trp) toward the R structure and toward the T structure, consistent with IHP causing a more pronounced decrease in its oxygen affinity. The results presented in this work, as well as other results recently reported in the literature, clearly indicate that there are multiple quaternary structures for the ligated form of hemoglobin. These results also provide new insights regarding the roles of allosteric effectors in regulating the structure and function of hemoglobin. The classical two-state/two-structure allosteric mechanism for the cooperative oxygenation of hemoglobin cannot account for the structural and functional properties of this protein and needs to be revised.

Allosteric Regulation↗
PubMed1995

Discriminating compact nonnative structures from the native structure of globular proteins.

Prediction of the native tertiary structure of a globular protein from the primary sequence will require a potential energy model that can discriminate all nonnative structures from the native structure(s). A successful model must distinguish not only alternate structures that are very nonnative but also alternate structures that are compact and near-native. We describe here a method, based on molecular dynamics simulation, that allows generation of hundreds of compact alternate structures that are arbitrarily close to the native structure. In this way, a significant amount of conformational space in the neighborhood of the native structure can be sampled and these alternate structures can be used as a stringent test of protein folding models. We have used two sets of these alternate structures generated for six crystallographically characterized small globular proteins (1200 alternate structures in all) to test eight empirical energy models for their ability to discriminate alternate from native structures. Seven of the models fail to correctly identify at least some of the alternate structures as nonnative. An atomic solvation model is presented that succeeds in discriminating all 1200 alternate structures from native.

Amino Acid Sequence↗
PubMed1999

Structure of taq DNA polymerase shows a new orientation for the structure-specific nuclease domain.

Thermus aquaticus DNA polymerase I consists of the polymerase, the structure-specific nuclease and the vestigial editing nuclease domains. Three-dimensional structures of the native enzyme and its complex with DNA have already been reported. The structure of a complex with an inhibitory antibody has also been determined. The structure of the native enzyme in a different crystal form determined at 2.6 A is reported here. Optimized anomalous diffraction measurements made at the holmium L(III) edge were valuable in validating solutions obtained through molecular replacement. The structure of the polymerase domain is similar to those reported previously, while the relative orientation of the structure-specific nuclease domain is significantly different from those of the native enzyme and the DNA complex; it is, however, identical to that observed in the structure of the Fab complex. In the structures of the native enzyme and of the DNA complex reported previously, the active site of the structure-specific nuclease domain is too far from that of the polymerase domain, making it difficult to propose a structural model for the in vivo primer-excision and nick-translation activities of the enzyme. In the present structure, the two active sites are considerably closer. Taken together, the reported structure of the native enzyme, that of the Fab complex and the present structure imply that the different orientation of the structure-specific nuclease domain is probably a consequence of intrinsically high relative mobility between these two domains in this enzyme.

Catalytic Domain↗
PubMed2003

High-pressure structural trends of Group 15 elements: simple packed structures versus complex host-guest arrangements.

The Group 15 elements P, As, Sb, and Bi all have layered structures consisting of six-membered rings under ambient conditions and attain the body-centered cubic (bcc) structure at the highest pressures applied. In the intermediate pressure region, however, phosphorus and its heavier congeners behave profoundly differently. In this region P first attains the open packed simple cubic (sc) structure for a wide range of pressures and then transforms into the rarely observed simple hexagonal (sh) structure. For the heavier congeners complex, incommensurately modulated host-guest structures emerge as intermediate pressure structures. We investigated the high-pressure behavior of P and As by ab initio density functional calculations in which pseudopotentials and a plane wave basis set were employed. The incommensurately modulated high-pressure structure of As was approximated by a supercell. Our calculations reproduced the experimentally established pressure stability ranges of the sc and sh structures for P and the host-guest structure for As very well. We found that the sc and especially the sh structure are decisively stabilized by the admixture of d states in the occupied levels of the electronic structure. This admixture releases s-s antibonding states above the Fermi level (s-d mixing). With pressure, s-d mixing increases rapidly for P, whereas it remains at a low level for As. As a consequence, the band energy contribution to the total energy determines the structural stability for P in the intermediate pressure region, giving rise to simple packed structures. On the other hand, in the intermediate pressure region of the heavier Group 15 elements, a delicate interplay between the electrostatic Madelung energy and the band energy leads to the formation of complex structures.

Journal Article↗
PubMed2005

Comparison of the predicted structures of loops in the ras-SOS protein bound to a single ras-p21 protein with the crystallographically determined structures in SOS bound to two ras-p21 proteins.

We have previously computed the structures of three loops, residues 591-596, 654-675 and 742-751, in the ras-p21 protein-binding domain (residues 568-1044) of the guanine nucleotide-exchange-promoting SOS protein that were crystallographically undefined when one molecule of ras-p21 (unbound to nucleotide) binds to SOS. Based on our computational results, we synthesized three peptides corresponding to sequences of each of these three loops and found that all three peptides strongly inhibit ras-p21 signaling. More recently, a new crystal structure of SOS has been determined in which this protein binds to two molecules of ras-p21, one unbound to GTP and one bound to GTP. In this structure, the 654-675 loop and residues 742-743 and 750-751 are now crystallographically defined. We have superimposed our energy-minimized structure of the ras-binding domain of SOS bound to one molecule of ras-p21 on the X-ray structure for SOS bound to two molecules of ras-p21. We find that, while the two structures are superimposable, there are large deviations of the residues 673 and 676 and 741 and 752, flanking the two loop segments. This suggests that the binding of the extra ras-p21 molecule, which is far from each of the three loops, induces conformational changes in these domains and further supports their role in signal transduction. In spite of these differences, we have superimposed our computed structures for the loop residues on those from the more recent X-ray structure. Our structure for the 654-675 segment is an anti-parallel beta-sheet with a reverse turn at residues 663-665; in the X-ray structure residues 655-662 adopt an alpha-helical conformation; on the other hand, our computed structure for residues 663-675 superimpose on the X-ray structure for these residues. We further find that our computed structures for residues 742-743 and 750-751 are superimposable on the X-ray structure for these residues.

Animals↗
PubMed2002

The solution structure of reduced dimeric copper zinc superoxide dismutase. The structural effects of dimerization.

The solution structure of homodimeric Cu2Zn2 superoxide dismutase (SOD) of 306 aminoacids was determined on a 13C, 15N and 70% 2H labeled sample. Two-thousand eight-hundred and five meaningful NOEs were used, of which 96 intersubunit, and 115 dihedral angles provided a family of 30 conformers with an rmsd from the average of 0.78 +/- 0.11 and 1.15 +/- 0.09 A for the backbone and heavy atoms, respectively. When the rmsd is calculated for each subunit, the values drop to 0.65 +/- 0.09 and 1.08 +/- 0.11 A for the backbone and heavy atoms, respectively. The two subunits are identical on the NMR time scale, at variance with the X-ray structures that show structural differences between the two subunits as well as between different molecules in the unit cell. The elements of secondary structure, i.e. eight beta sheets, are the same as in the X-ray structures and are well defined. The odd loops (I, III and V) are well resolved as well as loop II located at the subunit interface. On the contrary, loops IV and VI show some disorder. The residues of the active cavity are well defined whereas within the various subunits of the X-ray structure some are disordered or display different orientation in different X-ray structure determinations. The copper(I) ion and its ligands are well defined. This structure thus represents a well defined model in solution relevant for structure-function analysis of the protein. The comparison between the solution structure of monomeric mutants and the present structure shows that the subunit-subunit interactions increase the order in loop II. This has the consequences of inducing the structural and dynamic properties that are optimal for the enzymatic function of the wild-type enzyme. The regions 37-43 and 89-95, constituting loops III and V and the initial part of the beta barrel and showing several mutations in familial amyotrophis lateral sclerosis (FALS)-related proteins have a quite extensive network of H-bonds that may account for their low mobility. Finally, the conformation of the key Arg143 residue is compared to that in the other dimeric and monomeric structures as well as in the recently reported structure of the CCS-superoxide dismutase (SOD) complex.

Deuterium↗
PubMed2006

Application of protein structure alignments to iterated hidden Markov model protocols for structure prediction.

BACKGROUND: One of the most powerful methods for the prediction of protein structure from sequence information alone is the iterative construction of profile-type models. Because profiles are built from sequence alignments, the sequences included in the alignment and the method used to align them will be important to the sensitivity of the resulting profile. The inclusion of highly diverse sequences will presumably produce a more powerful profile, but distantly related sequences can be difficult to align accurately using only sequence information. Therefore, it would be expected that the use of protein structure alignments to improve the selection and alignment of diverse sequence homologs might yield improved profiles. However, the actual utility of such an approach has remained unclear. RESULTS: We explored several iterative protocols for the generation of profile hidden Markov models. These protocols were tailored to allow the inclusion of protein structure alignments in the process, and were used for large-scale creation and benchmarking of structure alignment-enhanced models. We found that models using structure alignments did not provide an overall improvement over sequence-only models for superfamily-level structure predictions. However, the results also revealed that the structure alignment-enhanced models were complimentary to the sequence-only models, particularly at the edge of the "twilight zone". When the two sets of models were combined, they provided improved results over sequence-only models alone. In addition, we found that the beneficial effects of the structure alignment-enhanced models could not be realized if the structure-based alignments were replaced with sequence-based alignments. Our experiments with different iterative protocols for sequence-only models also suggested that simple protocol modifications were unable to yield equivalent improvements to those provided by the structure alignment-enhanced models. Finally, we found that models using structure alignments provided fold-level structure assignments that were superior to those produced by sequence-only models. CONCLUSION: When attempting to predict the structure of remote homologs, we advocate a combined approach in which both traditional models and models incorporating structure alignments are used.

Algorithms↗
PubMed2003

Interrelationships between structural parameters of cancellous bone reveal accelerated structural change at low bone volume.

UNLABELLED: This study shows that change to cancellous bone structure is bone volume-dependent in a nonlinear manner. At low bone volume (< 15%), trabecular thickness and trabecular separation change at a much greater rate than at higher bone volume. This suggests that the structural integrity of the cancellous bone may become rapidly compromised when bone volume falls below a critical value. INTRODUCTION: While bone mass is the major determinant of bone strength, this mass-based paradigm does not fully account for the contribution of the bone microstructure to mechanical efficiency. Geometric models of cancellous bone structure have been formulated based on stylized representations of the trabecular elements, where the relationships between bone volume and bone surface of cancellous bone are complex and reflect the modulating effect on the cancellous bone structure of bone remodeling at the trabecular surfaces. Using the plate model of cancellous bone structure, the interrelationships between parameters of cancellous bone structure have been studied. MATERIALS AND METHODS: Two hundred eighty histological sections of human cancellous bone from eight skeletal sites were analyzed. The structural parameters of cancellous bone (BV/TV, BS/TV, BS/BV, Tb.Th, Tb.Sp, Tb.N, and TBPf) were obtained. RESULTS AND CONCLUSIONS: This study shows that change to cancellous bone structure is bone volume-dependent in a nonlinear manner. At low bone volume (< 15%), structural parameters of cancellous bone, such as trabecular thickness and trabecular separation, change at a much greater rate than at higher bone volume. This suggests that the structural integrity of the cancellous bone may become rapidly compromised when bone volume falls below a critical value. These data describe the complex relationships between bone mass and structure in cancellous bone that are often overlooked in the mass-based paradigm of bone strength. Histomorphometric descriptors of cancellous bone structure highlight the potential for accelerated deterioration of the structure with low bone volume, which leads to increased risk of fracture. From a clinical viewpoint, estimation of an individual's fracture risk is constrained to noninvasive techniques, which only provide bone mineral density or bone mineral content. Therefore, there is a need to better correlate measurement of bone mass with measurements of structural parameters.

Bone Density↗
PubMed2002

[Induction of petal-like structures from petals of Crocus sativus L. and the differentiation of style-stigma-like structures in vitro].

Firstly the petal of Crocus sativus L was cultured on the medium that supplemented with different combinations of hormones. The petal-like structures(PLS) were induced on medium, but the induction rates were different in various medium. The highest induction rate of petal-like structures was obtained on the media that was supplemented with NAA (4 mg/L) and KT (8 mg/L). The petal-like structures were subcultured on another media when the structure was produced on the explants and proliferate groups. The later media was used for inducing style-stigma-like structures(SSLS). The induction rate of style-stigma-like-structures in the petal-like structures group is much higher than the rate in the preceding work, and the maximum of style-stigma-like structures produced per explant was 30. The best result of style-stigma-like structures was observed on the petal-like structure groups which came from the third treatment. The differentiation rate of style-stigma-like structures is stable in the subcultures of petal-like structures. The result revealed that the induction frequency of style-stigma-like structures formed on the petal-like structures is higher than that form on the petals of C. sativus L.

Cell Differentiation↗
PubMed2000

The highly refined solution structure of the cytotoxic ribonuclease alpha-sarcin reveals the structural requirements for substrate recognition and ribonucleolytic activity.

alpha-Sarcin selectively cleaves a single phosphodiester bond in a universally conserved sequence of the major rRNA, that inactivates the ribosome. The elucidation of the three-dimensional solution structure of this 150 residue enzyme is a crucial step towards understanding alpha-sarcin's conformational stability, ribonucleolytic activity, and its exceptionally high level of specificity. Here, the solution structure has been determined on the basis of 2658 conformationally relevant distances restraints (including stereoespecific assignments) and 119 torsional angular restraints, by nuclear magnetic resonance spectroscopy methods. A total of 60 converged structures have been computed using the program DYANA. The 47 best DYANA structures, following restrained energy minimization by GROMOS, represent the solution structure of alpha-sarcin. The resulting average pairwise root-mean-square-deviation is 0.86 A for backbone atoms and 1.47 A for all heavy atoms. When the more variable regions are excluded from the analysis, the pairwise root-mean-square deviation drops to 0.50 A and 1.00 A, for backbone and heavy atoms, respectively. The alpha-sarcin structure is similar to that reported for restrictocin, although some differences are clearly evident, especially in the loop regions. The average rmsd between the structurally aligned backbones of the 47 final alpha-sarcin structures and the crystal structure of restrictocin is 1.46 A. On the basis of a docking model constructed with alpha-sarcin solution structure and the crystal structure of a 29-nt RNA containing the sarcin/ricin domain, the regions in the protein that could interact specifically with the substrate have been identified. The structural elements that account for the specificity of RNA recognition are located in two separate regions of the protein. One is composed by residues 51 to 55 and loop 5, and the other region, located more than 11 A away in the structure, is the positively charged segment formed by residues 110 to 114.

Allergens↗
PubMed1994

The 1.9 A structure of deoxy beta 4 hemoglobin. Analysis of the partitioning of quaternary-associated and ligand-induced changes in tertiary structure.

The crystal structure of the deoxygenated form of the human hemoglobin beta 4 tetramer (deoxy beta 4) has been determined and refined at a resolution of 1.9 A. A detailed comparison of the quaternary structures of carbonmonoxy-beta 4 (CO beta 4) and deoxy beta 4 shows that ligand binding to the beta 4 tetramer produces only slight movements of the subunits relative to each other. Therefore, unlike the hemoglobin alpha 2 beta 2 tetramer, where the transition from an unliganded T state tetramer to a liganded R state tetramer results in a large change in quaternary structure, beta 4 is locked in a quaternary structure that very closely resembles the R state. By comparing the high-resolution structures of T state deoxy alpha 2 beta 2, R state deoxy beta 4 and R state CO beta 4, it is possible to partition the changes in beta subunit tertiary structure into those that arise from changes in quaternary structure and those that result solely from ligand binding. Specifically, when viewed from the heme reference frame, comparison of the structures of T state deoxy alpha 2 beta 2 and R state deoxy beta 4 shows that the T-to-R quaternary structure transition induces changes in beta subunit tertiary structure that are approximately halfway toward the tertiary structure observed in liganded beta 4 and liganded alpha 2 beta 2. When viewed from the reference frame of the globin backbone atoms, the T-to-R quaternary structure transition induces a small rotation of the heme group and a shift of the "allosteric core" (the end of the F helix, the FG corner, the beginning of the G helix, and the heme group) away from the E helix. These movements open the ligand binding pocket and place the heme in a more symmetric position relative to the proximal histidine residue. Together, these effects work in unison to give the subunits of deoxy beta 4 a tertiary structure that has high ligand affinity.

Allosteric Site↗
PubMed1998

A Bayes-optimal sequence-structure theory that unifies protein sequence-structure recognition and alignment.

A rigorous Bayesian analysis is presented that unifies protein sequence-structure alignment and recognition. Given a sequence, explicit formulae are derived to select (1) its globally most probable core structure from a structure library; (2) its globally most probable alignment to a given core structure; (3) its most probable joint core structure and alignment chosen globally across the entire library; and (4) its most probable individual segments, secondary structure, and super-secondary structures across the entire library. The computations involved are NP-hard in the general case (3D-3D). Fast exact recursions for the restricted sequence singleton-only (1D-3D) case are given. Conclusions include: (a) the most probable joint core structure and alignment is not necessarily the most probable alignment of the most probable core structure, but rather maximizes the product of core and alignment probabilities; (b) use of a sequence-independent linear or affine gap penalty may result in the highest-probability threading not having the lowest score; (c) selecting the most probable core structure from the library (core structure selection or fold recognition only) involves comparing probabilities summed over all possible alignments of the sequence to the core, and not comparing individual optimal (or near-optimal) sequence-structure alignments; and (d) assuming uninformative priors, core structure selection is equivalent to comparing the ratio of two global means.

Amino Acid Sequence↗
PubMed2000

Evaluation of the utility of NMR structures determined from minimal NOE-based restraints for structure-based drug design, using MMP-1 as an example.

The application of deuterium labeling and residual dipolar coupling constants in combination with other structural information has demonstrated the potential for significantly expanding the range of viable protein targets for structural analysis by NMR. A previous study by Clore et al. [(1999) J. Am. Chem. Soc. 121, 6513-6514] demonstrated that a significant improvement in the overall protein structure occurs with the combination of residual dipolar coupling constants and minimal tertiary long-range distance restraints. The analysis of NMR protein structures determined with minimal structural information is extended with a particular interest in the utility of these structures for a structure-based drug design program. As an example, the catalytic fragment of human fibroblast collagenase (MMP-1) was used to follow the effect of minimal restraint sets on the protein structure and its utility in drug design with a particular interest in the effect on the active site conformation. An MMP-1 structure that was calculated with the maximal number of restraints attainable with the constraint of a deuterated protein was shown to be very similar to a high-quality MMP-1 structure that was calculated from a complete set of restraints. The superposition of the active site backbone atoms for the high-quality and minimal restraint MMP-1 structures yielded an rmsd of 0.68 A where the size and shape of the S1' pocket are nearly identical. Additionally, an MMP-1-CGS-27023A complex based on a minimal set of NOE-based restraints reliably reproduced the structure of the complex, establishing the usefulness of the structures for drug design.

Binding Sites↗
PubMed1998

Discrepancies between the NMR and X-ray structures of uncomplexed barstar: analysis suggests that packing densities of protein structures determined by NMR are unreliable.

The crystal structure of the C82A mutant of barstar, the intracellular inhibitor of the Bacillus amyloliquefaciens ribonuclease barnase, has been solved to a resolution of 2.8 A. The molecule crystallizes in the space group I41 with a dimer in the asymmetric unit. An identical barstar dimer is also found in the crystal structure of the barnase-barstar complex. This structure of uncomplexed barstar is compared to the structure of barstar bound to barnase and also to the structure of barstar solved using NMR. The free structure is similar to the bound state, and there are no significant main-chain differences in the 27-44 region involved in barstar binding to barnase. The C82A structure shows significant differences from the average NMR structure, both overall and in the binding region. In contrast to the crystal structure, the NMR structure shows an unusually high packing value based on the occluded surface algorithm, indicating errors in the packing of the structure. We show that the NMR structures of homologous proteins generally show large differences in packing value, while the crystal structures of such proteins have very similar packing values, suggesting that protein packing density is not well determined by NMR.

Alanine↗
PubMed1999

Using imperfect secondary structure predictions to improve molecular structure computations.

MOTIVATION: Until ab initio structure prediction methods are perfected, the estimation of structure for protein molecules will depend on combining multiple sources of experimental and theoretical data. Secondary structure predictions are a particularly useful source of structural information, but are currently only approximately 70% correct, on average. Structure computation algorithms which incorporate secondary structure information must therefore have methods for dealing with predictions that are imperfect. EXPERIMENTS PERFORMED: We have modified our algorithm for probabilistic least squares structural computations to accept 'disjunctive' constraints, in which a constraint is provided as a set of possible values, each weighted with a probability. Thus, when a helix is predicted, the distances associated with a helix are given most of the weight, but some weights can be allocated to the other possibilities (strand and coil). We have tested a variety of strategies for this weighting scheme in conjunction with a baseline synthetic set of sparse distance data, and compared it with strategies which do not use disjunctive constraints. RESULTS: Naive interpretations in which predictions were taken as 100% correct led to poor-quality structures. Interpretations that allow disjunctive constraints are quite robust, and even relatively poor predictions (58% correct) can significantly increase the quality of computed structures (almost halving the RMS error from the known structure). CONCLUSIONS: Secondary structure predictions can be used to improve the quality of three-dimensional structural computations. In fact, when interpreted appropriately, imperfect predictions can provide almost as much improvement as perfect predictions in three-dimensional structure calculations.

Algorithms↗
PubMed2005

PALSSE: a program to delineate linear secondary structural elements from protein structures.

BACKGROUND: The majority of residues in protein structures are involved in the formation of alpha-helices and beta-strands. These distinctive secondary structure patterns can be used to represent a protein for visual inspection and in vector-based protein structure comparison. Success of such structural comparison methods depends crucially on the accurate identification and delineation of secondary structure elements. RESULTS: We have developed a method PALSSE (Predictive Assignment of Linear Secondary Structure Elements) that delineates secondary structure elements (SSEs) from protein Calpha coordinates and specifically addresses the requirements of vector-based protein similarity searches. Our program identifies two types of secondary structures: helix and beta-strand, typically those that can be well approximated by vectors. In contrast to traditional secondary structure algorithms, which identify a secondary structure state for every residue in a protein chain, our program attributes residues to linear SSEs. Consecutive elements may overlap, thus allowing residues located at the overlapping region to have more than one secondary structure type. CONCLUSION: PALSSE is predictive in nature and can assign about 80% of the protein chain to SSEs as compared to 53% by DSSP and 57% by P-SEA. Such a generous assignment ensures almost every residue is part of an element and is used in structural comparisons. Our results are in agreement with human judgment and DSSP. The method is robust to coordinate errors and can be used to define SSEs even in poorly refined and low-resolution structures. The program and results are available at http://prodata.swmed.edu/palsse/.

Algorithms↗
PubMed2007

Ensemble docking of multiple protein structures: considering protein structural variations in molecular docking.

One approach to incorporate protein flexibility in molecular docking is the use of an ensemble consisting of multiple protein structures. Sequentially docking each ligand into a large number of protein structures is computationally too expensive to allow large-scale database screening. It is challenging to achieve a good balance between docking accuracy and computational efficiency. In this work, we have developed a fast, novel docking algorithm utilizing multiple protein structures, referred to as ensemble docking, to account for protein structural variations. The algorithm can simultaneously dock a ligand into an ensemble of protein structures and automatically select an optimal protein structure that best fits the ligand by optimizing both ligand coordinates and the conformational variable m, where m represents the m-th structure in the protein ensemble. The docking algorithm was validated on 10 protein ensembles containing 105 crystal structures and 87 ligands in terms of binding mode and energy score predictions. A success rate of 93% was obtained with the criterion of root-mean-square deviation <2.5 A if the top five orientations for each ligand were considered, comparable to that of sequential docking in which scores for individual docking are merged into one list by re-ranking, and significantly better than that of single rigid-receptor docking (75% on average). Similar trends were also observed in binding score predictions and enrichment tests of virtual database screening. The ensemble docking algorithm is computationally efficient, with a computational time comparable to that for docking a ligand into a single protein structure. In contrast, the computational time for the sequential docking method increases linearly with the number of protein structures in the ensemble. The algorithm was further evaluated using a more realistic ensemble in which the corresponding bound protein structures of inhibitors were excluded. The results show that ensemble docking successfully predicts the binding modes of the inhibitors, and discriminates the inhibitors from a set of noninhibitors with similar chemical properties. Although multiple experimental structures were used in the present work, our algorithm can be easily applied to multiple protein conformations generated by computational methods, and helps improve the efficiency of other existing multiple protein structure(MPS)-based methods to accommodate protein flexibility.

Algorithms↗