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At least 217 records · Page 12Linked to original sources
PubMed1995

Knowledge-based protein secondary structure assignment.

We have developed an automatic algorithm STRIDE for protein secondary structure assignment from atomic coordinates based on the combined use of hydrogen bond energy and statistically derived backbone torsional angle information. Parameters of the pattern recognition procedure were optimized using designations provided by the crystallographers as a standard-of-truth. Comparison to the currently most widely used technique DSSP by Kabsch and Sander (Biopolymers 22:2577-2637, 1983) shows that STRIDE and DSSP assign secondary structural states in 58 and 31% of 226 protein chains in our data sample, respectively, in greater agreement with the specific residue-by-residue definitions provided by the discoverers of the structures while in 11% of the chains, the assignments are the same. STRIDE delineates every 11th helix and every 32nd strand more in accord with published assignments.

Algorithms↗
PubMed2001

Carboplatin alone vs carboplatin plus epidoxorubicin as second-line therapy for cisplatin- or carboplatin-sensitive ovarian cancer.

OBJECTIVE: The aim of the study was to analyze the benefit/toxicity profile of a second-line treatment with carboplatin alone or carboplatin plus another non-cross-resistant drug (epidoxorubicin) in ovarian cancer patients sensitive to cisplatin-based chemotherapy at first-line treatment. METHODS: We conducted a randomized clinical trial. Women with epithelial ovarian cancer FIGO Stage II--IV who had a complete or partial response to first-line treatment with cisplatin or carboplatin-based regiments and subsequently progressed or relapsed more than 6 months after discontinuation of first-line treatment were eligible for the study. A total of 190 subjects entered the study. They were randomly allocated to either 300 mg/m(2) of carboplatin every 28 days for five cycles (95 patients) or 120 mg/m(2) of epidoxorubicin and 300 mg/m(2) of carboplatin every 28 days for five cycles (95 patients). RESULTS: A complete response was reported, respectively, in 32 (36%) women allocated to carboplatin alone and in 28 (31.8%) of those allocated to carboplatin plus epidoxorubicin. The corresponding figures for partial response were 18 (20.2%) and 26 (29.9%). Comparing the frequency of complete response, partial response, no change, and progression, the differences between the two groups were not significant (chi(2)(3) 5.10, P = 0.16). The median duration of response was 16 months in the carboplatin alone and 20 months in the carboplatin plus epidoxorubicin group (P = not significant). The 3-year percentage of survival was 29% in the carboplatin alone and 42% in the carboplatin plus epidoxorubicin group; this difference was not statistically significant. The frequency of leukopenia, anemia, and thrombocytopenia grade 3-4 was higher in the epidoxorubicin plus carboplatin than in the carboplatin alone group. Alopecia G3 was present in 88% of women treated with epidoxorubicin plus carboplatin. CONCLUSIONS: The general results of this study do not show any marked differences in response to second-line treatment among women treated with single-agent (carboplatin) or multiagent (carboplatin plus epidoxorubicin) schedules. Toxicity, particularly hematological, was more relevant in women treated with the multiagent schedule.

Adult↗
PubMed1993

Rotamers: to be or not to be? An analysis of amino acid side-chain conformations in globular proteins.

Originally, rotamers were defined as side-chain torsion (chi-angle) combinations corresponding to the local minima of potential energy (van-der-Waals and torsion terms) for the side-chain of a terminally blocked amino acid. If at least one chi-angle differed by more than 20 degrees from that of a rotamer, the side-chain was considered as deviant both from energetic (increase in potential energy of no less than 1 to 2 kcal/mol) and geometric (precision of atom positioning is worse than 0.5 A) aspects. In this work the distribution of side-chain conformations in protein crystal structures is analysed. Large deviations from rotameric chi-values occur systematically and cannot be attributed merely to errors in crystal structure determination. The "rotamericity" (the fraction of residues within +/- 20 degrees of the chi-angles of a rotamer) not only remains substantially below 100% (70 to 95% for various amino acids) with improving crystallographic resolution but actually decreases for 8 out of 17 amino acid types after a critical resolution limit is crossed. This effect has been observed for external as well as for internal residues. The set of amino acid side-chain conformations in globular proteins cannot be considered as normally distributed around some rotamer points. Outliers occur systematically. The rotamericity of an amino acid depends essentially on the different environments the amino acid meets in real protein structures. Factors such as the backbone torsion angles of the residue itself, the secondary structure and tertiary contacts influence the rotamericity. The deviations in regions of regular main-chain structure from the average g-:t:g+ relationship in the chi 1-angle become much more evident if, in addition to the typical secondary structure assignments, the actual backbone torsion angles of the residue are taken into account. In alpha-helices the t:g+ distribution in the chi 1-angle correlates with physical properties describing volume, extension and flexibility of the side-chain. In beta-strands the factors influencing the t:g+ distribution in the chi 1-angle are the polarity and hydrophobicity of the side-chain. Nevertheless, a considerable number of residues do not comply with the statistical preferences observed for the side-chain conformation. Large deviations from the rotamer values are observed especially in cases when normally advantageous chi 1-values are not allowed and adjustments in chi 2 become necessary to accommodate the side-chain.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acids↗
PubMed1993

A method to configure protein side-chains from the main-chain trace in homology modelling.

Protein homology modelling typically involves the prediction of side-chain conformations in the modelled protein while assuming a main-chain trace taken from a known tertiary structure of a protein with homologous sequence. It is generally believed that the need to examine all possible combinations of side-chain conformations poses the major obstacle to accurate homology modelling. Methods proposed heretofore use only discrete or limited searches of the side-chain torsion angle space to mitigate the combinatorial problem and also rely on simplified energy functions for calculational speed. The configurational constraints are typically based upon use of frequently observed torsion angles, fixed steps in torsion angles, or oligopeptide segments taken from tertiary structural databanks that are similar in sequence and conformation with the target structure. In the present work, a more fundamental approach is explored for several protein structures and it is demonstrated that the combinatorial barrier in side-chain placement hardly exists. Each side-group can be configured individually in the environment of only the backbone atoms using a systematic search procedure combined with extensive local energy minimization. Tests, using the main-chain or both the main-chain and remaining side-chain atoms to calculate low energy geometries for each residue, established the dominance of the main-chain contribution. The final structure is achieved by combining the individually placed side-chains followed by a full energy refinement of the structure. The prediction accuracy of the present homology modelling technique was assessed relative to other automated procedures and was found to yield improved predictions relative to the known side-chain conformations determined by X-ray crystallography.

Amino Acid Sequence↗
PubMed1994

Folding the main chain of small proteins with the genetic algorithm.

Grid-free protein folding simulations were effected using the genetic algorithm, a backbone representation and standard dihedral angular conformations. The topological folding of idealized four-helix bundles was investigated in detail to differentiate among the important protein folding forces used as fitness criteria. Hydrophobic interactions were the most significant while local forces and hydrogen bonds were far less effective in promoting folding. Stable secondary structural regions were also important as nucleating centers. Using the fitness parameters optimized in idealized simulations together with standard secondary structure predictions derived from the amino acid sequence alone, the proper main-chain folding of the four-helix bundle proteins cytochrome b562, cytochrome c' and hemerythrin was achieved. In addition the backbone topology as predicted by the genetic algorithm for crambin, a mixed helix/strand protein with known structure, is presented and discussed.

Algorithms↗
PubMed1994

Prediction of transmembrane segments in proteins utilising multiple sequence alignments.

A method for prediction of transmembrane segments from multiply aligned amino acid sequences is presented. For the calculations, two sets of propensity values were used: one for the middle, hydrophobic portion and one for the terminal regions of the transmembrane sequence spans. Average propensity values were calculated for each position along the alignment, with the contribution from each sequence weighted according to its dissimilarity relative to the other aligned sequences. Eight-residue segments were considered as potential cores of transmembrane segments and elongated if their middle propensity values were above a given threshold. End propensity values were also considered as stop signals. Only helices with length of 15 to 29 residues were allowed and corrections for strictly conserved charged residues were also made. The method is shown to be more successful than predictions based upon single sequences alone. In the test set of 28 families with 126 transmembrane segments, only five spans were not predicted or constituted false positives. The method is applied to sequence families for which data on transmembrane segments do not exist or are sparse or contradictory included voltage-gated potassium-channels, cytochrome c oxidases, NADH-ubiquinone oxidoreductase, beta-glucosides-specific phosphotransferase enzyme and major surface antigen of hepatitis B virus.

Algorithms↗
PubMed1994

The role of side-chain hydrogen bonds in the formation and stabilization of secondary structure in soluble proteins.

Intra-molecular side-chain:main-chain (sch:mch) and side-chain (sch:sch) hydrogen bonds observed in 44 well refined crystallographic protein structures with non-homologous sequences have been identified, classified and analysed to detect recurring structural patterns. Each observed bond was characterized by the position of its acceptor and donor groups relative to the N and C termini of the particular secondary structure in which they occur and according to their appearance within the same of sequentially separated secondary structures. The role of short-range hydrogen bonds in the formation and stabilization of a secondary structure and the importance of long-range hydrogen bonds as a cohesive force for different structural segments were also examined. It was found that the N terminus of alpha-helices is characterized by recurring sch:mch and sch:sch bonds with elements of the preceding coil segment, while at the C terminus a frequent intra-helix sch:mch hydrogen bond was frequently observed. The residues at or near the beta-strand termini often cross-linked, through hydrogen-bonding, non-sequential coil segments. Coil structures were characterized by recurring, internal sch:mch hydrogen bonding involving small polar side-chain groups situated at or near their N termini (coil N-capping). The significance of hydrogen bonds as formers and stabilizers of a protein fold and the association of its secondary structural units was also considered through an examination of bond density and distribution throughout the protein tertiary structure.

Amino Acids↗
PubMed1995

An assessment of amino acid exchange matrices in aligning protein sequences: the twilight zone revisited.

The sensitivity of most protein sequence alignment methods depends strongly on the quality of the comparison matrices used. These matrices, which assign weights or similarity scores to every possible amino acid substitution pair, are utilized to differentiate amongst the various possible alignments of two or more sequences. There are many ways to generate these exchange weights and new matrices are constantly published. There has been no overall assessment of these various matrices when applied in different alignment techniques and over many protein folds and families, both close and distant and with the use of several gap penalty values. In this work, a set of amino acid sequences matched by superposition of known protein tertiary topologies is used to test the alignment accuracy of the different method/matrix/penalty combinations. The comparisons show relatively similar results for the top scoring matrices, a preference for the global alignment method of Needleman and Wunsch, and the importance of matrix modification and optimized gap penalties. The relationship between the percentage identity in a resulting alignment and the level of correctness to be expected are given for the top-performing matrix, resulting in a better definition of the so-called "twilight zone". Estimates are made for the probability that two sequences, aligned at a certain level of residue percentage identity, are in fact unrelated.

Amino Acid Sequence↗
PubMed1996

Principles of helix-helix packing in proteins: the helical lattice superposition model.

The geometry of helix-helix packing in globular proteins is comprehensively analysed within the model of the superposition of two helix lattices which result from unrolling the helix cylinders onto a plane containing points representing each residue. The requirements for the helix geometry (the radius R, the twist angle omega and the rise per residue delta) under perfect match of the lattices are studied through a consistent mathematical model that allows consideration of all possible associations of all helix types (alpha-, pi- and 3(10)). The corresponding equations have three well-separated solutions for the interhelical packing angle, omega, as a function of the helix geometric parameters allowing optimal packing. The resulting functional relations also show unexpected behaviour. For a typically observed alpha-helix (omega = 99.1 degrees, delta = 1.45 A), the three optimal packing angles are omega a,b,c = -37.1 degrees, -97.4 degrees and +22.0 degrees with a periodicity of 180 degrees and respective helix radii Ra,b,c = 3.0 A, 3.5 A and 4.3 A. However, the resulting radii are very sensitive to variations in the twist angle omega. At omega triple = 96.9 degrees, all three solutions yield identical radii at delta = 1.45 A where Rtriple = 3.46 A. This radius is close to that of a poly(Ala) helix, indicating a great packing flexibility when alanine is involved in the packing core, and omega triple is close to the mean observed twist angle. In contrast, the variety of possible theoretical solutions is limited for the other two helix types. Besides the perfect matches, novel suboptimal "knobs into holes" hydrophobic packing patterns as a function of the helix radius are described. Alternative "knobs onto knobs" and mixed models can be applied in cases where salt bridges, hydrogen bonds, disulphide bonds and tight hydrophobic head-to-head contacts are involved in helix-helix associations. An analysis of the experimentally observed packings in proteins confirmed the conclusions of the theoretical model. Nonetheless, the observed alpha-helix packings showed deviations from the 180 degrees periodicity expected from the model. An investigation of the actual three-dimensional geometry of helix-helix packing revealed an explanation for the observed discrepancies where a decisive role was assigned to the defined orientation of the C alpha-C beta vectors of the side-chains. As predicted form the model, helices with different radii (differently sized side-chains in the packing core) were observed to utilize different packing cells (packing patterns). In agreement with the coincidence between Rtriple and the radius of a poly(Ala) helix, Ala was observed to show greatest propensity to build the packing core. The application of the helix lattice superposition model suggests that the packing of amino acid residues is best described by a "knobs into holes" scheme rather than "ridges into grooves". The various specific packing modes made salient by the model should be useful in protein engineering and design.

Algorithms↗
PubMed1996

Identifying the tertiary fold of small proteins with different topologies from sequence and secondary structure using the genetic algorithm and extended criteria specific for strand regions.

Grid-free protein folding simulations based on sequence and secondary structure knowledge (using mostly experimentally determined secondary structure information but also analysing results from secondary structure predictions) were investigated using the genetic algorithm, a backbone representation, and standard dihedral angular conformations. Optimal structures are selected according to basic protein building principles. Having previously applied this approach to proteins with helical topology, we have now developed additional criteria and weights for beta-strand-containing proteins, validated them on four small beta-strand-rich proteins with different topologies, and tested the general performance of the method on many further examples from known protein structures with mixed secondary structural type and less than 100 amino acid residues. Topology predictions close to the observed experimental structures were obtained in four test cases together with fitness values that correlated with the similarity of the predicted topology to the observed structures. Root-mean-square deviation values of C alpha atoms in the superposed predicted and observed structures, the latter of which had different topologies, were between 4.5 and 5.5 A(2.9 to 5.1 A without loops). Including 15 further protein examples with unique folds, root-mean-square deviation values ranged between 1.8 and 6.9 A with loop regions and averaged 5.3 A and 4.3 A, including and excluding loop regions, respectively.

Algorithms↗
PubMed1996

A functional role for protein cavities in domain: domain motions.

Motions between individual domains are known to play an important role in protein function. Protein cavities at domain interfaces have been suggested to facilitate such movements. Consequently, the cavity morphology in a set of multi-domain proteins has been critically examined. The conformational changes were well characterised by atomic resolution tertiary structures prior to and after domain motions. The results showed that interdomain cavities play a number of specific functional roles by either facilitating, or being otherwise involved with, domain: domain motions. Correspondingly, a higher fraction of cavity surface is observed at domain interfaces as compared to that buried within individual domains. Furthermore, interdomain cavity-forming residues were found to be highly conserved in terms of amino acid residue sequence and volume within their aligned protein families, more so than residues exclusive to the domain interface and intradomain cavities. These results provide substantial evidence of cavities fulfilling a specific functional role in multi-domain proteins.

Amino Acid Sequence↗
PubMed1997

Protein thermal stability, hydrogen bonds, and ion pairs.

Researchers in both academia and industry have expressed strong interest in comprehending the mechanisms responsible for enhancing the thermostability of proteins. Many and different structural principles have been postulated for the increased stability. Here, 16 families of proteins with different thermal stability were theoretically examined by comparing their respective fractional polar atom surface areas and the number and type of hydrogen bonds and salt links between explicit protein atoms. In over 80% of the families, correlations were found between the thermostability of the familial members and an increase in the number of hydrogen bonds as well as an increase in the fractional polar surface which results in added hydrogen bonding density to water. Thus increased hydrogen bonding may provide the most general explanation for thermal stability in proteins. The number of ion pairs was also found to increase with thermal stability in two-thirds of the families tested; however, their rate of addition was only about one-sixth that for internal hydrogen bonds amongst the protein atoms. The preferred residue exchanges and surface atom types useful in engineering enhanced stability were also examined.

Animals↗
PubMed1997

Olfaction in zebrafish: what does a tiny teleost tell us?

Zebrafish, Danio rerio, possess a well-developed sense of smell which governs a variety of behaviors. Both the number of odorant receptor genes and the number of modules in the olfactory bulb (glomeruli) are about an order of magnitude smaller than those of mammals. Nevertheless, the spatial organization of functional properties within the sensory surface and the olfactory bulb are comparable to those of mammals. The quantitatively reduced olfactory system of zebrafish, together with the suitability of this species for developmental and genetic studies, make zebrafish an interesting model system to study olfactory differentiation and neuronal representation of olfactory information.

Journal Article↗
PubMed1978

The taxonomy of binding sites in proteins.

Conservation of polypeptide fold and mode of ligand binding is frequently found within proteins of related function. Examples illustrating this phenomenon are taken from NAD linked enzymes, nucleotide binding proteins, polysaccharide binding proteins, heme binding proteins and enzymes with essential Fe--S complexes or zinc atoms.

Amino Acid Sequence↗
PubMed1983

The structure of bovine rhodopsin.

We have isolated 16 peptides from a cyanogen bromide digest of rhodopsin. These cyanogen bromide peptides account for the complete composition of the protein. Methionine-containing peptides from other chemical and enzymatic digests of rhodopsin have allowed us to place the cyanogen bromide peptides in order, yielding the sequence of the protein. We have completed the sequence of most of the cyanogen bromide peptides. This information, in conjunction with that from other laboratories, forms the basis for our prediction of the secondary structure of the protein and how it may be arranged in the disk membrane.

Amino Acid Sequence↗
PubMed1992

Non-cytopathic infection of rhabdomyosarcoma cells by coxsackie B5 virus.

Infection of rhabdomyosarcoma (RD) cells by coxsackie B5 virus (CBV5) was non-cytopathic, although low titres of infectious virus were produced after 24 h post-infection. The extent of CBV5 replication in RD cells increased after sequential passage of the virus in these cells. The RD cells from the first cycle of CBV5 infection were recovered and maintained in culture for 3 months (equivalent to 21 passages) releasing infectious virus throughout this period; these cells were considered to be persistently infected with CBV5 and were designated piRD cells. Coxsackie virus antigen was demonstrated in a small proportion of piRD cells by immunofluorescence staining. High resolution two-dimensional polyacrylamide gel electrophoresis was used to analyse the intracellular proteins prepared from piRD cells, three proteins were detected which were absent in uninfected RD cells. These new proteins were similar in charge to virus proteins induced during CBV5 lytic infection of HEp-2 cells. Quantitative densitometry of 2-dimensional protein profiles of piRD and uninfected cells showed no significant disruption of RD cell protein synthesis by the persistent virus infection. Three cloned cell lines were recovered from piRD cells, none of which showed evidence of infectious virus or virus-induced protein synthesis suggesting that the parental cell line was a carrier culture for CBV5.

Antigens, Viral↗
PubMed1980

A structural comparison of concanavalin A and tomato bushy stunt virus protein.

Significant structural equivalence has been found among the polypeptide folds of the two tomato bushy stunt virus (TBSV) subunit domains and concanavalin A. This suggests gene duplication in the TBSV coat protein and leads to speculation on common functional properties of concanavalin A and viral coat proteins.

Chemical Phenomena↗
PubMed2003

Diagnostic and therapeutic laparoscopy for nonpalpable testis.

BACKGROUND: We evaluated the use of laparoscopy in the management of impalpable testis to determine what advantages it might offer over the open approach. METHODS: Over a 5.5-year period, a total of 46 patients with 53 nonpalpable testes underwent a laparoscopic procedure at our hospital. There were 28 cases of intraabdominal testis (52.83%), 18 cases of the vas and vessels entering the internal ring (33.96%), and seven cases of intraabdominally absent testis (13.20%). We performed a laparoscopic orchiopexy for 24 testes (scrotal in 21 cases and partial to the inguinal canal in three cases) and an orchiectomy for three testes. We encountered inguinal hernia in 14 cases (26.41%). RESULTS: At follow-up, all testes were the same size as at the time of operation and were well positioned in the scrotum, except for four testes that required reoperation due to partial migration at the superficial inguinal ring. The operating time was <1 h in unilateral cases and <2 h for the bilateral cases. All procedures were completed successfully without conversion or complications. CONCLUSIONS: Laparoscopy is the only exploratory procedure that is accurate enough to enable the diagnosis of nonpalpable testis and also allow the surgical treatment to be done in the same setting.

Abdomen↗