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PubMed2005

A structural alphabet for local protein structures: improved prediction methods.

Three-dimensional protein structures can be described with a library of 3D fragments that define a structural alphabet. We have previously proposed such an alphabet, composed of 16 patterns of five consecutive amino acids, called Protein Blocks (PBs). These PBs have been used to describe protein backbones and to predict local structures from protein sequences. The Q16 prediction rate reaches 40.7% with an optimization procedure. This article examines two aspects of PBs. First, we determine the effect of the enlargement of databanks on their definition. The results show that the geometrical features of the different PBs are preserved (local RMSD value equal to 0.41 A on average) and sequence-structure specificities reinforced when databanks are enlarged. Second, we improve the methods for optimizing PB predictions from sequences, revisiting the optimization procedure and exploring different local prediction strategies. Use of a statistical optimization procedure for the sequence-local structure relation improves prediction accuracy by 8% (Q16 = 48.7%). Better recognition of repetitive structures occurs without losing the prediction efficiency of the other local folds. Adding secondary structure prediction improved the accuracy of Q16 by only 1%. An entropy index (Neq), strongly related to the RMSD value of the difference between predicted PBs and true local structures, is proposed to estimate prediction quality. The Neq is linearly correlated with the Q16 prediction rate distributions, computed for a large set of proteins. An "expected" prediction rate QE16 is deduced with a mean error of 5%.

Amino Acid Sequence↗
PubMed1992

Structural effects induced by mutagenesis affected by crystal packing factors: the structure of a 30-51 disulfide mutant of basic pancreatic trypsin inhibitor.

The X-ray structure of the C30V/C51A disulfide mutant of basic pancreatic trypsin inhibitor (BPTI) has been analyzed at 1.6 A resolution. The mutant crystallizes in a cell having two molecules in the asymmetric unit. The packing environments of these two molecules are quite different, allowing for an assessment of which among the observed structural changes result from the mutation and which are produced by lattice packing considerations. The removal of the 30-51 disulfide bridge has little apparent affect on the B-factors of segments of adjacent polypeptide chain, although there are distinct differences in the structure compared to wild-type BPTI crystal structures. Both of the two C30V/C51A molecules show differences at the mutation site when compared to another 30-51 disulfide mutant, C30A/C51A, presumably due to the larger steric bulk of a valine versus an alanine at residue 30. A comparison of the two independent C30V/C51A molecules indicates that there are significant differences between them even at the site of mutation. The description of the specific structural differences of each molecule differs in detail and suggests different conclusions about the nature of structural perturbation near 30-51. In addition, when these two molecules are compared to two different wild-type structures, which had been determined from different space groups, a somewhat different pattern of changes is observed. These findings indicate that crystal packing can influence the observed perturbations in mutant structures.

Alanine↗
PubMed1998

Solution structure of Desulfovibrio vulgaris (Hildenborough) ferrocytochrome c3: structural basis for functional cooperativity.

Desulfovibrio vulgaris cytochrome c3 is a 14 kDa tetrahaem cytochrome that plays a central role in energy transduction. The three-dimensional structure of the ferrocytochrome at pH 8.5 was solved through two-dimensional 1H-NMR. The structures were calculated using a large amount of experimental information, which includes upper and lower distance limits as well as dihedral angle restraints. The analysis allows for fast-flipping aromatic residues and flexibility in the haem plane. The structure was determined using 2289 upper and 2390 lower distance limits, 63 restricted ranges for the phi torsion angle, 88 stereospecific assignments out of the 118 stereopairs with non-degenerate chemical shifts (74.6%), and 115 out of the 184 nuclear Overhauser effects to fast-flipping aromatic residues (62.5%), which were pseudo-stereospecifically assigned to one or the other side of the ring. The calculated NMR structures are very well defined, with an average root-mean-square deviation value relative to the mean coordinates of 0.35 A for the backbone atoms and 0.70 A for all heavy-atoms. Comparison of the NMR structures of the ferrocytochrome at pH 8.5 with the available X-ray structure of the ferricytochrome at pH 5.5 reveals that the general fold of the molecule is very similar, but that there are some distinct differences. Calculation of ring current shifts for the residues with significantly different conformations confirms that the NMR structures represent better its solution structure in the reduced form. Some of the localised differences, such as a reorientation of Thr24, are thought to be state-dependent changes that involve alterations in hydrogen bond networks. An important rearrangement in the vicinity of the propionate groups of haem I and involving the covalent linkage of haem II suggests that this is the critical region for the functional cooperativities of this protein.

Amino Acid Sequence↗
PubMed1998

NMR structure of the Streptomyces metalloproteinase inhibitor, SMPI, isolated from Streptomyces nigrescens TK-23: another example of an ancestral beta gamma-crystallin precursor structure.

The Streptomyces metalloproteinase inhibitor, SMPI, isolated from Streptomyces nigrescens TK-23, is a proteinaceous metalloproteinase inhibitor, and consists of 102 amino acid residues with two disulfide bridges. SMPI specifically inhibits metalloproteinases such as thermolysin. In the present work, the solution structure of SMPI was determined on the basis of 1536 nuclear Overhauser enhancement derived distance restraints and 52 dihedral angle restraints obtained from three-bond spin coupling constants. The final ensemble of 20 NMR structures overlaid onto their mean coordinate with backbone (N, Calpha, C') r.m.s.d. values of 0. 45(+/-0.11) A and 0.57(+/-0.18) A for residues 6 to 99 and the entire 102 residues, respectively. SMPI is essentially composed of two beta-sheets, each consisting of four antiparallel beta-strands. The structure can be considered as two Greek key motifs with 2-fold internal symmetry, a Greek key beta-barrel. One unique structural feature found in SMPI is in its extension between the first and second strands of the second Greek key motif. Interestingly, this extended segment is known to be involved in the inhibitory activity of SMPI. In the absence of sequence similarity, the SMPI structure shows clear similarity to both domains of the eye lens crystallins, both domains of the calcium sensor protein-S, as well as the single-domain yeast killer toxin. The yeast killer toxin structure was thought to be a precursor of the two-domain beta gamma-crystallin proteins, because of its structural similarity to each domain of the beta gamma-crystallins. SMPI thus provides another example of a single-domain protein structure that corresponds to the ancestral fold from which the two-domain proteins in the beta gamma-crystallin superfamily are believed to have evolved.

Amino Acid Sequence↗
PubMed2001

Crystal structure of native and Cd/Cd-substituted Dioclea guianensis seed lectin. A novel manganese-binding site and structural basis of dimer-tetramer association.

Diocleinae legume lectins are a group of oligomeric proteins whose subunits display a high degree of primary structure and tertiary fold conservation but exhibit considerable diversity in their oligomerisation modes. To elucidate the structural determinants underlaying Diocleinae lectin oligomerisation, we have determined the crystal structures of native and cadmium-substituted Dioclea guianensis (Dguia) seed lectin. These structures have been solved by molecular replacement using concanavalin (ConA) coordinates as the starting model, and refined against data to 2.0 A resolution. In the native (Mn/Ca-Dguia) crystal form (P4(3)2(1)2), the asymmetric unit contains two monomers arranged into a canonical legume lectin dimer, and the tetramer is formed with a symmetry-related dimer. In the Cd/Cd-substituted form (I4(1)22), the asymmetric unit is occupied by a monomer. In both crystal forms, the tetrameric association is achieved by the corresponding symmetry operators. Like other legume lectins, native D. guianensis lectin contains manganese and calcium ions bound in the vicinity of the saccharide-combining site. The architecture of these metal-binding sites (S1 and S2) changed only slightly in the cadmium/cadmium-substituted form. A highly ordered calcium (native lectin) or cadmium (Cd/Cd-substituted lectin) ion is coordinated at the interface between dimers that are not tetrameric partners in a similar manner as the previously identified Cd(2+) in site S3 of a Cd/Ca-ConA. An additional Mn(2+) coordination site (called S5), whose presence has not been reported in crystal structures of any other homologous lectin, is present in both, the Mn/Ca and the Cd/Cd-substituted D. guianensis lectin forms. On the other hand, comparison of the primary and quaternary crystal structures of seed lectins from D. guianensis and Dioclea grandiflora (1DGL) indicates that the loop comprising residues 117-123 is ordered to make interdimer contacts in the D. grandiflora lectin structure, while this loop is disordered in the D. guianensis lectin structure. A single amino acid difference at position 131 (histidine in D. grandiflora and asparagine in D. guianensis) drastically reduces interdimer contacts, accounting for the disordered loop. Further, this amino acid change yields a conformation that may explain why a pH-dependent dimer-tetramer equilibrium exists for the D. guianensis lectin but not for the D. grandiflora lectin.

Binding Sites↗
PubMed2006

Sequence representation and prediction of protein secondary structure for structural motifs in twilight zone proteins.

Characterizing and classifying regularities in protein structure is an important element in uncovering the mechanisms that regulate protein structure, function and evolution. Recent research concentrates on analysis of structural motifs that can be used to describe larger, fold-sized structures based on homologous primary sequences. At the same time, accuracy of secondary protein structure prediction based on multiple sequence alignment drops significantly when low homology (twilight zone) sequences are considered. To this end, this paper addresses a problem of providing an alternative sequences representation that would improve ability to distinguish secondary structures for the twilight zone sequences without using alignment. We consider a novel classification problem, in which, structural motifs, referred to as structural fragments (SFs) are defined as uniform strand, helix and coil fragments. Classification of SFs allows to design novel sequence representations, and to investigate which other factors and prediction algorithms may result in the improved discrimination. Comprehensive experimental results show that statistically significant improvement in classification accuracy can be achieved by: (1) improving sequence representations, and (2) removing possible noise on the terminal residues in the SFs. Combining these two approaches reduces the error rate on average by 15% when compared to classification using standard representation and noisy information on the terminal residues, bringing the classification accuracy to over 70%. Finally, we show that certain prediction algorithms, such as neural networks and boosted decision trees, are superior to other algorithms.

Algorithms↗
PubMed1992

Structure of a fluid dioleoylphosphatidylcholine bilayer determined by joint refinement of x-ray and neutron diffraction data. III. Complete structure.

We present in this paper the complete structure of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) in the L alpha phase (66% RH, 23 degrees C) obtained by the joint refinement of neutron and x-ray lamellar diffraction data. The structural details obtained have previously required a large number of neutron diffraction experiments, using numerous specifically-deuterated phospholipid isomorphs (Büldt et al., 1978. Nature (Lond.). 271:182-184). The joint-refinement approach minimizes specific deuteration by utilizing independent neutron and x-ray data sets. The method yields a quasimolecular structure consisting of a series of multiatomic fragments that are each represented by one or several Gaussian distributions whose positions and widths can be determined to within 0.06 to 0.52 A exclusive of the methylene region. The image of DOPC at 66% RH (5.36 +/- 0.08 waters per lipid) is consistent with many aspects of bilayer structure previously determined by structural and spectroscopic studies. The most striking feature of the structure is the large amount of transbilayer thermal motion suggested by the widths and overlaps of the Gaussian envelopes of the quasimolecular fragments. We discuss the "dynamic bilayer thickness" which describes the minimum effective thickness of the hydrocarbon permeability barrier in terms of the thermal motion of the water. A gradient of thermal motion exists that increases in either direction away from the glycerol backbone which is the most constrained portion of the bilayer. The steric interactions between headgroups of apposed bilayers, expected at the hydration level of our experiments, are clearly revealed. A useful consequence of the quasimolecular structure is that average boundaries within bilayers calculated using composition and volumetric data and ad hoc assumptions can be related to the positions of the principal structural groups. Several measures of "bilayer thickness" in common use can be identified as the positions of the cholines for Luzzati's d1 (Luzzati and Husson. 1962. J. Cell Biol. 12:207-219) and the glycerols for Small's dL (Small. 1967. J. Lipid Res. 8:551-556). We do not know if these relations will be true at other hydrations or for other lipids. Of particular interest is the fact that the position of the carbonyl groups marks the average hydrocarbon/headgroup boundary. It must be emphasized, however, that this region of the bilayer must be generally characterized as one of tumultuous chemical heterogeneity because of the thermal motion of the bilayer.

Biophysical Phenomena↗
PubMed2002

Structural basis for thermophilic protein stability: structures of thermophilic and mesophilic malate dehydrogenases.

The three-dimensional structure of four malate dehydrogenases (MDH) from thermophilic and mesophilic phototropic bacteria have been determined by X-ray crystallography and the corresponding structures compared. In contrast to the dimeric quaternary structure of most MDHs, these MDHs are tetramers and are structurally related to tetrameric malate dehydrogenases from Archaea and to lactate dehydrogenases. The tetramers are dimers of dimers, where the structures of each subunit and the dimers are similar to the dimeric malate dehydrogenases. The difference in optimal growth temperature of the corresponding organisms is relatively small, ranging from 32 to 55 degrees C. Nevertheless, on the basis of the four crystal structures, a number of factors that are likely to contribute to the relative thermostability in the present series have been identified. It appears from the results obtained, that the difference in thermostability between MDH from the mesophilic Chlorobium vibrioforme on one hand and from the moderate thermophile Chlorobium tepidum on the other hand is mainly due to the presence of polar residues that form additional hydrogen bonds within each subunit. Furthermore, for the even more thermostable Chloroflexus aurantiacus MDH, the use of charged residues to form additional ionic interactions across the dimer-dimer interface is favored. This enzyme has a favorable intercalation of His-Trp as well as additional aromatic contacts at the monomer-monomer interface in each dimer. A structural alignment of tetrameric and dimeric prokaryotic MDHs reveal that structural elements that differ among dimeric and tetrameric MDHs are located in a few loop regions.

Amino Acid Sequence↗
PubMed1998

Structural features of halophilicity derived from the crystal structure of dihydrofolate reductase from the Dead Sea halophilic archaeon, Haloferax volcanii.

BACKGROUND: The proteins of halophilic archaea require high salt concentrations both for stability and for activity, whereas they denature at low ionic strength. The structural basis for this phenomenon is not yet well understood. The crystal structure of dihydrofolate reductase (DHFR) from Haloferax volcanii (hv-DHFR) reported here provides the third example of a structure of a protein from a halophilic organism. The enzyme is considered moderately halophilic, as it retains activity and secondary structure at monovalent salt concentrations as low as 0.5 M. RESULTS: The crystal structure of hv-DHFR has been determined at 2.6 A resolution and reveals the same overall fold as that of other DHFRs. The structure is in the apo state, with an open conformation of the active-site gully different from the open conformation seen in other DHFR structures. The unique feature of hv-DHFR is a shift of the alpha helix encompassing residues 46-51 and an accompanied altered conformation of the ensuing loop relative to other DHFRs. Analysis of the charge distribution, amino acid composition, packing and hydrogen-bonding pattern in hv-DHFR and its non-halophilic homologs has been performed. CONCLUSIONS: The moderately halophilic behavior of hv-DHFR is consistent with the lack of striking structural features expected to occur in extremely halophilic proteins. The most notable feature of halophilicity is the presence of clusters of non-interacting negatively charged residues. Such clusters are associated with unfavorable electrostatic energy at low salt concentrations, and may account for the instability of hv-DHFR at salt concentrations lower than 0.5 M. With respect to catalysis, the open conformation seen here is indicative of a conformational transition not reported previously. The impact of this conformation on function and/or halophilicity is unknown.

Amino Acid Sequence↗
PubMed2004

Toward the insulin-IGF-I intermediate structures: functional and structural properties of the [TyrB25NMePheB26] insulin mutant.

The origins of differentiation of insulin from insulin-like growth factor I (IGF-I) are still unknown. To address the problem of a structural and biological switch from the mostly metabolic hormonal activity of insulin to the predominant growth factor activities of IGF-I, an insulin analogue with IGF-I-like structural features has been synthesized. Insulin residues Phe(B25) and Tyr(B26) have been swapped with the IGF-I-like Tyr(24) and Phe(25) sequence with a simultaneous methylation of the peptide nitrogen of residue Phe(B26). These modifications were expected to introduce a substantial kink in the main chain, as observed at residue Phe(25) in the IGF-I crystal structure. These alterations should provide insight into the structural origins of insulin-IGF-I structural and functional divergence. The [Tyr(B25)NMePhe(B26)] mutant has been characterized, and its crystal structure has been determined. Surprisingly, all of these changes are well accommodated within an insulin R6 hexamer. Only one molecule of each dimer in the hexamer responds to the structural alterations, the other remaining very similar to wild-type insulin. All alterations, modest in their scale, cumulate in the C-terminal part of the B-chain (residues B23-B30), which moves toward the core of the insulin molecule and is associated with a significant shift of the A1 helix toward the C-terminus of the B-chain. These changes do not produce the expected bend of the main chain, but the fold of the mutant does reflect some structural characteristics of IGF-1, and in addition establishes the CO(A19)-NH(B25) hydrogen bond, which is normally characteristic of T-state insulin.

Animals↗
PubMed1997

NMR solution structure of a two-disulfide derivative of charybdotoxin: structural evidence for conservation of scorpion toxin alpha/beta motif and its hydrophobic side chain packing.

The alpha/beta scorpion fold consisting of a short alpha-helix and beta-sheet is a structural motif common to scorpion toxins, insect defensins, and plant gamma-thionins that invariably contains three disulfides. CHABII is a two-disulfide derivative of the scorpion toxin charybdotoxin (ChTX), chemically synthesized by inserting two L-alpha-aminobutyric acids in place of the two half-cystine residues involved in the disulfide 13-33. This disulfide is one of the two disulfides which connect the alpha-helix to the beta-sheet. The solution structure of CHABII was determined at pH 6.3 and 5 degrees C using 2D NMR and simulated annealing from 513 distance and 46 dihedral angle constraints. The NMR structure of CHABII is well-defined as judged from the low value of the averaged backbone rms deviation between the 30 lowest energy structures and the energy-minimized mean structure ((rmsd) = 0.65 A for the entire sequence and 0.48 A for the segment 3-36). Analysis and comparison of the solution structures of CHABII and ChTX lead to the following conclusions: (i) the fold of CHABII is similar to that of ChTX as indicated by the low value of the averaged backbone atomic rms deviation between the 10 lowest energy solution structures of the two proteins (1.44 A); (ii) the packing of the hydrophobic core is well-preserved, underlying the critical structural role of the hydrophobic interactions even for such a small and cysteine-rich protein as ChTX.

Amino Acid Sequence↗
PubMed2003

Comparative analysis of mt LSU rRNA secondary structures of Odonates: structural variability and phylogenetic signal.

Secondary structures of the most conserved part of the mt 16S rRNA gene, domains IV and V, have been recently analysed in a comparative study. However, full secondary structures of the mt LSU rRNA molecule are published for only a few insect species. The present study presents full secondary structures of domains I, II, IV and V of Odonates and one representative of mayflies, Ephemera sp. The reconstructions are based on a comparative approach and minimal consensus structures derived from sequence alignments. The inferred structures exhibit remarkable similarities to the published Drosophila melanogaster model, which increases confidence in these structures. Structural variance within Odonates is homoplastic, and neighbour-joining trees based on tree edit distances do not correspond to any of the phylogenetically expected patterns. However, despite homoplastic quantitative structural variation, many similarities between Odonates and Ephemera sp. suggest promising character sets for higher order insect systematics that merit further investigations.

Animals↗
PubMed2005

Structural genomics analysis of alternative splicing and application to isoform structure modeling.

Alternative splicing is a sophisticated nuclear process that regulates gene expression. It represents an important mechanism for enhancing the functional diversity of proteins. Our current knowledge of alternatively spliced variants is derived mainly from mRNA transcripts, and very little is known about their protein tertiary structures. We carried out a large-scale analysis of known alternatively spliced variants at both protein sequence and structure levels and have shown that threading is, in general, a viable approach for modeling structures of alternatively spliced variants. An examination of alternative splicing at the protein sequence level revealed that the size of splicing events follows the power law distribution and the majority of splicing isoforms harbor only one or two alternations. We examined alternative splicing in the context of protein 3D structures and found that the boundaries of alternative splicing events generally happen in coil regions of secondary structures and exposed residues and the majority of the sequences involved in splicing are located on the surface of proteins. In light of these findings, we then proceeded to demonstrate that threading represents a useful tool for structure prediction of alternative splicing isoforms and addressed the fold stability issue of threading-based structure prediction by molecular dynamics simulation. Our analysis and the insights gained have helped to establish a viable method for structure prediction of alternatively spliced isoforms at the genome scale.

Alternative Splicing↗
PubMed1999

Crystal structure of human T cell leukemia virus type 1 gp21 ectodomain crystallized as a maltose-binding protein chimera reveals structural evolution of retroviral transmembrane proteins.

Retroviral entry into cells depends on envelope glycoproteins, whereby receptor binding to the surface-exposed subunit triggers membrane fusion by the transmembrane protein (TM) subunit. We determined the crystal structure at 2.5-A resolution of the ectodomain of gp21, the TM from human T cell leukemia virus type 1. The gp21 fragment was crystallized as a maltose-binding protein chimera, and the maltose-binding protein domain was used to solve the initial phases by the method of molecular replacement. The structure of gp21 comprises an N-terminal trimeric coiled coil, an adjacent disulfide-bonded loop that stabilizes a chain reversal, and a C-terminal sequence structurally distinct from HIV type 1/simian immunodeficiency virus gp41 that packs against the coil in an extended antiparallel fashion. Comparison of the gp21 structure with the structures of other retroviral TMs contrasts the conserved nature of the coiled coil-forming region and adjacent disulfide-bonded loop with the variable nature of the C-terminal ectodomain segment. The structure points to these features having evolved to enable the dual roles of retroviral TMs: conserved fusion function and an ability to anchor diverse surface-exposed subunit structures to the virion envelope and infected cell surface. The structure of gp21 implies that the N-terminal fusion peptide is in close proximity to the C-terminal transmembrane domain and likely represents a postfusion conformation.

Amino Acid Sequence↗
PubMed2004

Structural basis for coronavirus-mediated membrane fusion. Crystal structure of mouse hepatitis virus spike protein fusion core.

The surface transmembrane glycoprotein is responsible for mediating virion attachment to cell and subsequent virus-cell membrane fusion. However, the molecular mechanisms for the viral entry of coronaviruses remain poorly understood. The crystal structure of the fusion core of mouse hepatitis virus S protein, which represents the first fusion core structure of any coronavirus, reveals a central hydrophobic coiled coil trimer surrounded by three helices in an oblique, antiparallel manner. This structure shares significant similarity with both the low pH-induced conformation of influenza hemagglutinin and fusion core of HIV gp41, indicating that the structure represents a fusion-active state formed after several conformational changes. Our results also indicate that the mechanisms for the viral fusion of coronaviruses are similar to those of influenza virus and HIV. The coiled coil structure has unique features, which are different from other viral fusion cores. Highly conserved heptad repeat 1 (HR1) and HR2 regions in coronavirus spike proteins indicate a similar three-dimensional structure among these fusion cores and common mechanisms for the viral fusion. We have proposed the binding regions of HR1 and HR2 of other coronaviruses and a structure model of their fusion core based on our mouse hepatitis virus fusion core structure and sequence alignment. Drug discovery strategies aimed at inhibiting viral entry by blocking hairpin formation may be applied to the inhibition of a number of emerging infectious diseases, including severe acute respiratory syndrome.

Amino Acid Motifs↗
PubMed2005

Solution structure of synthetic penaeidin-4 with structural and functional comparisons with penaeidin-3.

Antimicrobial peptide structure has direct implications for the complexity of functions and mechanisms of action. The penaeidin antimicrobial peptide family from shrimp is divided into multiple class designations based on primary structure. The penaeidin classes are not only characterized by variability in primary sequence but also by variation in target specificity and effectiveness. Whereas class 4 exhibits low isoform diversity within species and is highly conserved between species, the primary sequence of penaeidin class 3 is less conserved between species and exhibits considerable isoform diversity within species. All penaeidins, regardless of class or species, are composed of two dramatically different domains: an unconstrained proline-rich domain and a disulfide bond-stabilized cysteine-rich domain. The proline-rich domain varies in length and is generally less conserved, whereas the spacing and specific residue content of the cysteine-rich domain is more conserved. The structure of the synthetic penaeidin class 4 (PEN4-1) from Litopenaeus setiferus was analyzed using several approaches, including chemical mapping of disulfide bonds, circular dichroism analysis of secondary structural characteristics, and complete characterization of the solution structure of the peptide by proton NMR. L. setiferus PEN4-1 was then compared with the previously characterized structure of penaeidin class 3 from Litopenaeus vannamei. Moreover, the specificity of these antimicrobial peptides was examined through direct comparison of activity against a panel of microbes. The penaeidin classes differ in microbial target specificity, which correlates to variability in specific domain sequence. However, the tertiary structure of the cysteine-rich domain and indeed the overall structure of penaeidins are conserved across classes.

Amino Acid Sequence↗
PubMed2001

Structure-activity relationships for non-congeneric structures. Application of substructural balance method for antiallergic activity.

This paper presents a new research method of structure-activity relationships (SAR) based on the concept of substructural balance. By using antiallergic activity (PCA, rat, iv) of a non-congeneric set of 267 structures, the structural feature of active group is expressed in terms of substructural balance. Each structure was expressed with 100 new substructures and the number of each substructure in a molecule was counted. The substructural balance was expressed as their ratio. Structures were classified into three groups based on their potencies (ED50), active (44), median (33) and inactive (190) group. Using two substructural ratios, 80.53% of inactive and 57.58% of median structures were excluded from those that were active. Common features of active structures were shown as a zone indicating the optimal ranges of two substructural ratios. Two substructural ratios were determined out of 4950 substructural ratios, all possible combinations of 100 substructures (100C2), by selecting the greatest discriminatory power of inactive from active structures. The substructures used in this work include: the number of bonds comprising of the longest conjugate system, the number of skeletal atoms and the numbers of electron-donor pairs at certain distances in the molecule.

Animals↗
PubMed2000

Sequence-structure specificity of a knowledge based energy function at the secondary structure level.

MOTIVATION: This paper investigates the sequence-structure specificity of a representative knowledge based energy function by applying it to threading at the level of secondary structures of proteins. Assessing the strengths and weaknesses of an energy function at this fundamental level provides more detailed and insightful information than at the tertiary structure level and the results obtained can be useful in tertiary level threading. RESULTS: We threaded each of the 293 non-redundant proteins onto the secondary structures contained in its respective native protein (host template). We also used 68 pairs of proteins with similar folds and low sequence identity. For each pair, we threaded the sequence of one protein onto the secondary structures of the other protein. The discerning power of the total energy function and its one-body, pairwise, and mutation components is studied. We then applied our energy function to a recent study which demonstrated how a designed 11-amino acid sequence can replace distinct segments (one segment is an alpha-helix, the other is a beta-sheet) of a protein without changing its fold. We conducted random mutations of the designed sequence to determine the patterns for favorable mutations. We also studied the sequence-structure specificity at the boundaries of a secondary structure. Finally, we demonstrated how to speed up tertiary level threading by filtering out alignments found to be energetically unfavorable during the secondary structure threading. AVAILABILITY: The program is available on request from the authors. CONTACT: xud@ornl.gov

Amino Acid Sequence↗