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At least 253 records · Page 14Linked to original sources
PubMed1989

Engineering protein thermal stability. Sequence statistics point to residue substitutions in alpha-helices.

Amino acid sequences have been compared for thermophilic and mesophilic molecules from six different protein families, which include lactate and glyceraldehyde-3-phosphate dehydrogenases, triose phosphate isomerases, superoxide dismutases, thermolysins and subtilisins. Since a three-dimensional structure was known for at least one of the sequences in each family, analysis of preferred residue substitutions, presumably to achieve thermal stability, could be examined from a structural context. The overall results, which are generally consistent across all the families, suggested decreased flexibility and increased hydrophobicity in alpha-helical regions as the main stabilizing principles. The most favoured residual exchanges, hopefully useful in engineering stability into proteins, are discussed.

Amino Acid Sequence↗
PubMed1990

An investigation of oligopeptides linking domains in protein tertiary structures and possible candidates for general gene fusion.

Fifty-one examples of oligopeptides linking protein domains were extracted from the Brookhaven database of three-dimensional protein structures. In general, the peptides displayed specific characteristics in composition, conformation, hydrogen bonding, flexibility and the like. The entire database was then searched for pentapeptides that would optimize these natural linker properties. The oligopeptides found are suggested as general candidates to link protein molecules or domains through gene fusion.

Amino Acid Sequence↗
PubMed1990

Evolution of protein cores. Constraints in point mutations as observed in globin tertiary structures.

The amino acid sequences of ten globin chain tertiary structures were aligned and structurally equivalenced by spatial superposition of main-chain C alpha atoms. A search was then performed for structurally equivalent residue pairs that were buried in the protein core and that had mutated but maintained similar unmutated environments. Residues with atoms in contact with such central residue pairs define their environments. Such examples of point mutations would represent in vivo site-directed mutagenesis as would be observed in evolution. A search for mutated but exposed equivalent central residues was also performed. The constraints placed on the characteristics of the mutated residues (e.g., side-chain volume, polarity, radius of gyration) allow suggestions for the evolutionary modes of protein core and surface development as well as residue substitution guidelines to maintain structural stability in protein engineering and design.

Amino Acid Sequence↗
PubMed1990

Protruding domain of tomato bushy stunt virus coat protein is a hitherto unrecognized class of jellyroll conformation.

The capsid protein of tomato bushy stunt virus (TBSV) has two antiparallel beta-sheet domains with the so-called jellyroll conformation. Contrary to previous analyses, we note that these domains are non-superimposable topologies. The TBSV shell (S) domain topology is common to many other proteins but the protruding (P) domain is a unique conformation so far found in no other protein. The TBSV capsid P domain did not arise from the S domain by a gene duplication event as previously assumed. It is proposed instead that the P domain was acquired from an as yet unidentified cellular protein. The four possible unique jellyroll topologies that might occur in proteins are discussed and illustrated.

Capsid↗
PubMed1991

Side-chain clusters in protein structures and their role in protein folding.

A method has been developed to detect dense clusters of residue side-chains in proteins, where contact is based upon the percentage of the maximum possible for a given residue type. The clusters represent protein sites with the highest degree of interaction amongst their member residues, while contacts with the environment surrounding the cluster are lower in number. The method has been applied to three distinct structural sets of proteins to check for consistency: mixed alpha-helical/beta-sheet proteins, all beta-strand proteins, and all alpha-helical proteins. A number of cluster features generated from these sets are of general interest for protein folding. (1) A majority of the clusters, comprising three to four residues on average, are localized near the protein surfaces and not within the protein cores. (2) The clusters have preferences for the N- and C-terminal ends of alpha-helices and beta-strands in alpha/beta and alpha-proteins, while beta-proteins utilize the middle strand regions more often. A number of clusters connect three or more beta-strands and/or alpha-helices. (3) More than half of the clusters display residue pairs with oppositely charged atoms within 4.5 A of each other. (4) The residue composition of the clusters does not show correlation with hydrophobicity measures but rather with side-chain volume and surface. The highly preferred cluster residues are (in order of decreasing preference) Trp, His, Arg, Tyr, Glu, Gln and Phe. Clusters with extensive internal contacts in related haemoglobin and immunoglobulin tertiary structures show respective conservation. Several examples illustrate "strategic" folding positions in proteins that often bring together a number of sheets and/or helices, suggesting a folding model in which largely preformed secondary structures are joined together in a cluster induced collapse. Alternatively, the clusters may form at some stage in the folding process to reduce considerably the searchable conformational space and help maintain the proper folding pathway. The clusters also provide hints for site-directed mutagenesis and protein engineering experiments as they are also suggested to be important for structural stability.

Amino Acid Sequence↗
PubMed1991

Suggestions for "safe" residue substitutions in site-directed mutagenesis.

The conserved topological structure observed in various molecular families such as globins or cytochromes c allows structural equivalencing of residues in every homologous structure and defines in a coherent way a global alignment in each sequence family. A search was performed for equivalent residue pairs in various topological families that were buried in protein cores or exposed at the protein surface and that had mutated but maintained similar unmutated environments. Amino acid residues with atoms in contact with the mutated residue pairs defined the environment. Matrices of preferred amino acid exchanges were then constructed and preferred or avoided amino acid substitutions deduced. Given the conserved atomic neighborhoods, such natural in vivo substitutions are subject to similar constrains as point mutations performed in site-directed mutagenesis experiments. The exchange matrices should provide guidelines for "safe" amino acid substitutions least likely to disturb the protein structure, either locally or in its overall folding pathway, and most likely to allow probing the structural and functional significance of the substituted site.

Amino Acid Sequence↗
PubMed1991

Motif recognition and alignment for many sequences by comparison of dot-matrices.

Calculation of dot-matrices is a widespread tool in the search for sequence similarities. When sequences are distant, even this approach may fail to point out common regions. If several plots calculated for all members of a sequence set consistently displayed a similarity between them, this would increase its credibility. We present an algorithm to delineate dot-plot agreement. A novel procedure based on matrix multiplication is developed to identify common patterns and reliably aligned regions in a set of distantly related sequences. The algorithm finds motifs independent of input sequence lengths and reduces the dependence on gap penalties. When sequences share greater similarity, the same approach converts to a multiple sequence alignment procedure.

Algorithms↗
PubMed1992

Prediction of protein folding pathways.

Recent 1H nuclear magnetic resonance (n.m.r.) hydrogen exchange experiments on five different proteins have delineated the secondary structures formed in trapped, partially folded intermediates. The early forming structural elements are identifiable through a technique described in this work to predict folding pathways. The method assumes that the sequential selection of structural fragments such as alpha-helices and beta-strands involved in the folding process is founded upon the maximal burial of solvent accessible surface from both the formation of internal structure and substructure association. The substructural elements were defined objectively by major changes in main-chain direction. The predicted folding pathways are in complete correspondence with the n.m.r. results in that the formed structural fragments found in the folding intermediates are those predicted earliest in the pathways. The technique was also applied to proteins of known tertiary structure and with fold similar to one of the five proteins examined by 1H n.m.r. The pathways for these structures also showed general consistency with the n.m.r. observations, suggesting conservation of a secondary structural framework or molten globule about which folding nucleates and proceeds.

Amino Acid Sequence↗
PubMed1992

Anatomy and evolution of proteins displaying the viral capsid jellyroll topology.

In this paper the anatomy of 25 structures containing a jellyroll motif, consisting of eight antiparallel beta-strands forming a so-called beta-barrel, was investigated. This involved performing a careful structural alignment based on hydrogen bonds for the equivalent regions of the tertiary folds and a subsequent analysis of conserved amino acids, equivalenced residue-residue contacts, and various parameters describing the size, shape and other geometrical characteristics of these regions. It was found that the jellyroll motif is best viewed as a two-sheet wedge structure rather than a barrel. The more conserved parameters are discussed. A model of evolutionary development for the jellyroll fold in the various protein and viral structures is proposed.

Amino Acid Sequence↗
PubMed1992

Recognition of distantly related protein sequences using conserved motifs and neural networks.

A sensitive technique for protein sequence motif recognition based on neural networks has been developed. It involves three major steps. (1) At each appropriate alignment position of a set of N matched sequences, a set of N aligned oligopeptides is specified with preselected window length. N neural nets are subsequently and successively trained on N-1 amino acid spans after eliminating each ith oligopeptide. A test for recognition of each of the ith spans is performed. The average neural net recognition over N such trials is used as a measure of conservation for the particular windowed region of the multiple alignment. This process is repeated for all possible spans of given length in the multiple alignment. (2) The M most conserved regions are regarded as motifs and the oligopeptides within each are used to train intensively M individual neural networks. (3) The M networks are then applied in a search for related primary structures in a databank of known protein sequences. The oligopeptide spans in the database sequence with strongest neural net output for each of the M networks are saved and then scored according to the output signals and the proper combination that follows the expected N- to C-terminal sequence order. The motifs from the database with highest similarity scores can then be used to retrain the M neural nets, which can be subsequently utilized for further searches in the databank, thus providing even greater sensitivity to recognize distant familial proteins. This technique was successfully applied to the integrase, DNA-polymerase and immunoglobulin families.

Aldehyde Dehydrogenase↗
PubMed1992

Optimal protocol and trajectory visualization for conformational searches of peptides and proteins.

Conformational searches by molecular dynamics and different types of Monte Carlo or build-up methods usually aim to find the lowest-energy conformation. However, this is often misleading, as the energy functions used in conformational calculations are imprecise. For instance, though positions of local minima defined by the repulsive part of the Lennard-Jones potential are usually altered only slightly by functional modification, the relative depths of the minima could change significantly. Thus, the purpose of conformational searches and, correspondingly, performance criteria should be reformulated and appropriate methods found to extract different local minima from the search trajectory and allow visualization in the search space. Attempts at convergence to the lowest-energy structure should be replaced with efforts to visit a maximum number of different local energy minima with energies within a certain range. We use this quantitative criterion consistently to evaluate performances of different search procedures. To utilize information generated in the course of simulation, a "stack" of low energy conformations is created and stored. It keeps track of variables and visit numbers for the best representatives of different conformational families. To visualize the search, projection of multidimensional walks onto a principal plane defined by a set of reference structures is used. With Met-enkephalin as a structural example and a Monte Carlo procedure combined with energy minimization (MCM) as a basic search method, we analyzed the influence on search efficiency of different characteristics as temperature schedules, the step size for variable modification, constrained random step and response mechanisms to search difficulties. Simulated annealing MCM had comparable efficiency with MCM at constant and elevated temperature (about 600 K). Constraining the randomized choice of side-chain chi angles to optimal values (rotamers) on every MCM step did not improve, but rather worsened, the search efficiency. Two low-energy Met-enkephalin conformations with parallel Tyr1 and Phe4 rings, a gamma-turn around the Gly2 residue, and Phe4 and Met5 side-chains forming together a compact hydrophobic cluster were found and are suggested as possible structural candidates for interaction with a receptor or a membrane.

Amino Acid Sequence↗
PubMed1992

Analysis of insertions/deletions in protein structures.

An analysis of insertions and deletions (indels) occurring in a databank of multiple sequence alignments based on protein tertiary structure is reported. Indels prefer to be short (1 to 5 residues). The average intervening sequence length between them versus the percentage of residue identity in pairwise alignments shows an exponential behaviour, suggesting a stochastic process such that nearly every loop in an ancestral structure is a possible target for indels during evolution. The results also suggest a limit to the average size of indels accommodated by protein structures. The preferred indel conformations are reverse turn and coil as are the preferred conformations at the indel edges (N- and C-terminal sides). Interruptions in helices and strands were observed as very rare events.

Amino Acid Sequence↗
PubMed1985

Turnip yellow mosaic virus and its capsid have thermal stabilities with opposite pH dependence: studies by differential scanning calorimetry and 31P nuclear magnetic resonance spectroscopy.

In the differential scanning calorimetry (DSC) scans of turnip yellow mosaic virus (TYMV) or its capsid a single endotherm was observed. The endotherm was attributed to disruption of the virion or capsid structure with accompanying protein denaturation. At pH 4.5 the thermal stabilities of the TYMV virion and capsid were similar. With increasing pH, the capsid stability increased while the virion stability decreased. At neutral pH the capsid disrupted at 83.5 degrees, and the virion disrupted at 69 degrees. Our results suggest that packaging of viral RNA in the TYMV capsid imparts instability. The pHmid for disruption of the TYMV capsid is 5.7, which is in the pKa range expected for histidine side chains. Hence repulsive interactions involving one or more of the three histidines of the TYMV coat protein may explain the decreased stability of the TYMV capsid at low pH. This conclusion is supported further by the observation that belladonna mottle virus (BDMV) capsid (BDMV and TYMV belong to the tymo virus group), which contains no histidine in its coat protein, did not exhibit pH-dependent stability. The size of the cooperative unit in the disruption of TYMV capsid was estimated to be approximately that of a dimer of the coat protein, at pH 7.0, but a larger oligomer at low pH. Several reports implicate pH-dependent protein-RNA interactions with a pHmid near 7 as important in stabilizing tymovirus virions. Both DSC and 31P nuclear magnetic resonance linewidth analyses of the TYMV virion showed a transition midpoint at pH 7.0.

Calorimetry, Differential Scanning↗
PubMed1986

Primary structural relationships may reflect similar DNA replication strategies.

The primary structures of several proteins of bacterial and viral origin involved in the initiation of DNA synthesis and its subsequent elongation were compared. It was found that the known sequences of DNA polymerases and the single-stranded DNA binding proteins from phage T7 and Escherichia coli aligned well. Furthermore, segmental homologies were found in the phage phi 29 and adenovirus polymerases as well as in their DNA binding proteins. These results suggest similar mechanisms of DNA synthesis for E. coli and T7 on the one hand and for phi 29 and adenovirus on the other.

Adenoviruses, Human↗
PubMed1984

Rhodopsin's protein and carbohydrate structure: selected aspects.

A topographic model for rhodopsin has been constructed based upon evaluation of rhodopsin's sequence by a secondary structure prediction algorithm as well as chemical and enzymatic modification of rhodopsin in the membrane [Hargrave et al. (1983) Biophys. Struct. Mech. 9, 235-244]. The non-uniform distribution of several amino acids in the primary structure and within the topographic model is discussed. The seven predicted helices were evaluated and each helix was found to have one surface which is much more hydrophobic than the other. Stereoscopic views of a three dimensional model with a functional color-coding scheme incorporating these features are presented. The amino acid sequence of rhodopsin has been compared to other proteins in the Dayhoff Protein Data Bank. No obvious relationship to any other protein sequenced was found. High resolution proton magnetic resonance spectroscopy was used to reinvestigate the structure and relative proportions of rhodopsin's major and minor oligosaccharide chains. One major (Man3GlcNAc3) and two minor (Man4GlcNAc3 and Man5GlcNAc3) were observed.

Amino Acid Sequence↗