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Results for “Protein Structure, Tertiary”

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PubMed2000

How to generate improved potentials for protein tertiary structure prediction: a lattice model study.

Success in the protein structure prediction problem relies heavily on the choice of an appropriate potential function. One approach toward extracting these potentials from a database of known protein structures is to maximize the Z-score of the database proteins, which represents the ability of the potential to discriminate correct from random conformations. These optimization methods model the entire distribution of alternative structures, reducing their ability to concentrate on the lowest energy structures most competitive with the native state and resulting in an unfortunate tendency to underestimate the repulsive interactions. This leads to reduced accuracy and predictive ability. Using a lattice model, we demonstrate how we can weight the distribution to suppress the contributions of the high-energy conformations to the Z-score calculation. The result is a potential that is more accurate and more likely to yield correct predictions than other Z-score optimization methods as well as potentials of mean force.

Algorithms↗
PubMed1997

Protein phi and psi dihedral restraints determined from multidimensional hypersurface correlations of backbone chemical shifts and their use in the determination of protein tertiary structures.

The chemical shifts of the backbone atoms of proteins can be used to obtain restraints that can be incorporated into structure determination methods. Each chemical shift can be used to define a restraint and these restraints can be simultaneously used to define the local, secondary structure features. The global fold can be determined by a combined use of the chemical shift based restraints along with the long-range information present in the NOEs of partially deuterated proteins or the amide-amide NOEs but not from such limited NOE data sets alone. This approach has been demonstrated to be capable of determining the overall folding pattern of four proteins. This suggests that solution-state NMR methods can be extended to the structure determination of larger proteins by using the information present in the chemical shifts of the backbone atoms along with the data that can be obtained on a small number of labeled forms.

Amino Acids↗
PubMed1998

Selective bridging of bis-cysteinyl residues by arsonous acid derivatives as an approach to the characterization of protein tertiary structures and folding pathways by mass spectrometry.

Bis-cysteine selective modifications were successfully applied with melarsen oxide (MEL), an arsonous acid derivative, for tertiary structural studies of peptides and a model protein. The arsonous acid modified peptides and proteins were amenable to direct characterizations by mass spectrometry, e.g., direct molecular weight determinations and mass spectrometric peptide mapping that identified stoichiometry and sites of modification, respectively. Proteolytic digestion and mass spectrometric fragmentation of modified oxytocin showed that MEL-bridged peptide derivatives are structural homologues to the disulfide-bonded macrocyclic peptides. Mass spectrometric analyses determined the MEL modification site in partially reduced and selectively modified bovine pancreatic trypsin inhibitor (BPTI) bridging Cys-14 and Cys-38. The BPTI.MEL derivative was resistant to proteolysis by both Lys-C and trypsin and thus represented a rigid structure like native BPTI. MEL exhibited several advantageous features such as (i) cross-linking two closely spaced thiol groups, providing detailed tertiary structure information; (ii) high solubility as monomeric ortho acid in aqueous and organic solutions; (iii) adding a relatively large mass increment to proteins upon single modification; (iv) enabling UV monitoring of the derivatization due to a strong chromophor; and (v) performing fast and specific modifications of bis-thiol groups in proteins to form stable structures without any side reactions even with a high molar excess of MEL. The investigated physical and chemical properties of MEL suggest general applicability for selective bis-thiol modifications, enabling protein structure-function studies in both soluble and membrane proteins and the study of protein-folding reactions.

Amino Acid Sequence↗
PubMed1993

Constructive induction and protein tertiary structure prediction.

To date, the only methods that have been used successfully to predict protein structures have been based on identifying homologous proteins whose structures are known. However, such methods are limited by the fact that some proteins have similar structure but no significant sequence homology. We consider two ways of applying machine learning to facilitate protein structure prediction. We argue that a straightforward approach will not be able to improve the accuracy of classification achieved by clustering by alignment scores alone. In contrast, we present a novel constructive induction approach that learns better representations of amino acid sequences in terms of physical and chemical properties. Our learning method combines knowledge and search to shift the representation of sequences so that semantic similarity is more easily recognized by syntactic matching. Our approach promises not only to find new structural relationships among protein sequences, but also expands our understanding of the roles knowledge can play in learning via experience in this challenging domain.

Artificial Intelligence↗
PubMed1994

An algorithm to generate low-resolution protein tertiary structures from knowledge of secondary structure.

An algorithm is described to assemble the three-dimensional fold of a protein starting from its secondary structure. A reduced representation of the polypeptide chain is used together with a crude potential based on pair hydrophobicities. The method is shown to be successful in locating the native topology for two 4-alpha-helix bundles, myohemerythrin and cytochrome b-562.

Algorithms↗
PubMed1991

Generalized protein tertiary structure recognition using associative memory Hamiltonians.

In previous papers, a method of protein tertiary structure recognition was described based on the construction of an associative memory Hamiltonian, which encoded the amino acid sequence and the C alpha co-ordinates of a set of database proteins. Using molecular dynamics with simulated annealing, the ability of the Hamiltonian to successfully recall the structure of a protein in the memory database was successfully demonstrated, as long as the total number of database proteins did not exceed a characteristic value, called the capacity of the Hamiltonian, equal to 0.5N to 0.7N, where N is the number of amino acid residues in the protein to be recalled. In this paper, we describe the development of additional methods to increase the capacity of the Hamiltonian, including use of a more complete representation of the protein backbone and the incorporation of contextual information into the Hamiltonian through the use of secondary structure prediction. In addition, we further extend the ability of associative memory models to predict the tertiary structures of proteins not present in the protein data set, by making the Hamiltonian invariant with respect to biological symmetries that represent site mutations and insertions and deletions. The ability of the Hamiltonian to generalize from homologous proteins to an unknown protein in the presence of other unrelated proteins in the data set is demonstrated.

Cytochromes↗
PubMedDate not supplied

Molecular characterization of surface topology in protein tertiary structures by amino-acylation and mass spectrometric peptide mapping.

Amino-acetylation and -succinylation reactions in combination with mass spectrometric peptide mapping of tryptic peptide mixtures have been employed for surface topology-probing of lysine residues in bovine ribonuclease A, lysozyme, and horse heart myoglobin as model proteins of different surface structures. Direct molecular weight determinations identifying the precise number of acyl groups in partially modified proteins were obtained by electrospray and 252Cf-plasma desorption mass spectrometry. Electrospray mass spectra of multiply protonated molecular ions and deuterium exchange experiments provided a relative conformational characterization of protein derivatives and enabled the direct determinations of intact, partially acylated heme-myoglobin derivatives. Tryptic peptide mapping analysis, using plasma desorption and fast atom bombardment mass spectrometry, ascertained by mass spectrometric characterization of HPLC-separated modified peptides, yielded the exact identification of acylation sites. Relative reactivities of the amino acylation were derived from the peptide mapping data and from quantitative estimations of modified peptides upon acetylation/trideuteroacetylation and provided direct correlations with the relative surface accessibilities of lysine-epsilon-amino groups taken from X-ray crystallographic structure data of the proteins. The reactive lysine-41 residue in ribonuclease A which is part of the substrate binding site was directly identified from the mass spectrometric data. These results indicate tertiary structure-selective acylation combined with mass spectrometric peptide mapping as an efficient approach for the molecular characterization of surface topology and reactive fundamental lysine residues in proteins.

Acylation↗
PubMed1995

Reduced representation approach to protein tertiary structure prediction: statistical potential and simulated annealing.

A reduced representation model has been developed and used to predict the folded structures of proteins from their primary sequences and random starting conformations. The molecular structure of each protein is reduced to its backbone atoms (with ideal fixed bond lengths and valence angles) and each side chain approximated by a single virtual united atom. The co-ordinate variables are the backbone dihedral angles phi and psi. A statistical potential function, which includes local and non-local interactions and is computed from known X-ray elucidated protein structures, is used in the structure minimization. Simulated annealing method of energy minimization is employed to search for folded conformations. Simulations using the reduced representation model reproduce many structural features of the studied proteins.

Computer Simulation↗
PubMed1994

Identification of important functional environs in protein tertiary structures from the analysis of residue variation in 3-D: application to cytochromes c and carboxypeptidases A and B.

A simple methodology is described to apply to aligned protein sequence sets for which at least one representative 3-D C alpha structure is known. The evolutionary variation observed at each residue position in the sequence alignment is qualified by taking into account the residue variation that has occurred at other positions located within 7 A (according to the probable chain fold). This expresses the evolutionary behaviour of any residue position in the more appropriate context of its immediate surroundings and distinguishes between invariant residues on the basis of the variation of their environment. The highest mechanistic significance is attached to conserved residues in conserved surroundings, but the quantitative nature of the analysis means that all residue vicinities can be ranked and merged according to the degree of conservation that they exhibit and the residue positions that comprise them. Therefore, with the aid of the chain fold, contour maps can be constructed that show graded foci of evolutionary conservation in the underlying superstructure of the protein type, and the irregular shapes and extents of large conserved areas. To test the methodology, it was applied to cytochromes c and the carboxypeptidases A and B.

Biological Evolution↗
PubMed1997

ESCHER: a new docking procedure applied to the reconstruction of protein tertiary structure.

Evaluation of Surface Complementarity, Hydrogen bonding, and Electrostatic interaction in molecular Recognition (ESCHER) is a new docking procedure consisting of three modules that work in series. The first module evaluates the geometric complementarity and produces a set of rough solutions for the docking problem. The second module identifies molecular collisions within those solutions, and the third evaluates their electrostatic complementarity. We describe the algorithm and its application to the docking of cocrystallized protein domains and unbound components of protein-protein complexes. Furthermore, ESCHER has been applied to the reassociation of secondary and supersecondary structure elements. The possibility of applying a docking method to the problem of protein structure prediction is discussed.

Protein Structure, Secondary↗
PubMed2005

TASSER: an automated method for the prediction of protein tertiary structures in CASP6.

The recently developed TASSER (Threading/ASSembly/Refinement) method is applied to predict the tertiary structures of all CASP6 targets. TASSER is a hierarchical approach that consists of template identification by the threading program PROSPECTOR_3, followed by tertiary structure assembly via rearranging continuous template fragments. Assembly occurs using parallel hyperbolic Monte Carlo sampling under the guide of an optimized, reduced force field that includes knowledge-based statistical potentials and spatial restraints extracted from threading alignments. Models are automatically selected from the Monte Carlo trajectories in the low-temperature replicas using the clustering program SPICKER. For all 90 CASP targets/domains, PROSPECTOR_3 generates initial alignments with an average root-mean-square deviation (RMSD) to native of 8.4 A with 79% coverage. After TASSER reassembly, the average RMSD decreases to 5.4 A over the same aligned residues; the overall cumulative TM-score increases from 39.44 to 52.53. Despite significant improvements over the PROSPECTOR_3 template alignment observed in all target categories, the overall quality of the final models is essentially dictated by the quality of threading templates: The average TM-scores of TASSER models in the three categories are, respectively, 0.79 [comparative modeling (CM), 43 targets/domains], 0.47 [fold recognition (FR), 37 targets/domains], and 0.30 [new fold (NF), 10 targets/domains]. This highlights the need to develop novel (or improved) approaches to identify very distant targets as well as better NF algorithms.

Algorithms↗
PubMed1994

Determination of protein tertiary structure class from circular dichroism spectra.

Fifty-three circular dichroism (CD) spectra consisting of the spectra of 46 native proteins, 3 denatured proteins, and one oligopeptide (the spectra of two denatured proteins and oligopeptide were taken at two different temperatures) were investigated in order to examine the correlation between the shape of the CD spectrum and the tertiary structure class of the protein. Five classes were considered--all -alpha, all -beta, alpha+beta, alpha/beta, and denatured proteins. Spectra from 190 to 236 nm with 2 nm interval were described as points in 24-dimensional hyperspace, where coordinates were values of ellipticities at fixed wavelengths. This allows the spectra to be treated as patterns and subsequently analyzed using pattern recognition algorithms. Cluster analysis, which does not need predefined information about protein structure, divides spectra into several compact groups or clusters with good correlation with tertiary structure class. To visualize these results, orthogonalization procedures were imposed on the original data set in 24-dimensional space. The new 3-dimensional coordinate system demonstrated well-separated all-beta class and denatured proteins. Regions corresponding to all -alpha and especially alpha+beta and alpha/beta proteins were not as well resolved. The following approach was then applied to the original data set to obtain an objective mathematical algorithm for the determination of a protein's tertiary structure class from its CD spectrum. Regions in 24-dimensional hyperspace corresponding to all of the tertiary structure classes were found by calculating the decision functions, or equations of hyperplanes, which separate groups of spectral patterns of different classes.(ABSTRACT TRUNCATED AT 250 WORDS)

Algorithms↗
PubMed1978

On the formation of protein tertiary structure on a computer.

In this paper we carry out computer simulation studies of some of the factors responsible for protein tertiary structure. We show that it is possible to obtain (fold) a compact globular conformation from a sequence of amino acids consisting of only glycines and alanines. Our results indicate that glycines play a central role in stabilizing globular structures by facilitating the formation of turns and by destabilizing helical structures. Using this simple two-amino-acid representation, which serves as a control experiment, we are able to obtain a conformation that resembles the native structure of pancreatic trypsin inhibitor, as closely as any obtained previously in folding studies. However, careful examination reveals that the true chain topology has not been reproduced here or in previous studies. We suggest that the discrepancies between calculated and observed structures are more significant than the similarities. The implications of these results for the validity of models for protein folding, the use of pancreatic trypsin inhibitor in folding studies, and the possible role of glycine in the evolution of protein structure are discussed.

Alanine↗
PubMed2004

An all-atom force field for tertiary structure prediction of helical proteins.

We have developed an all-atom free-energy force field (PFF01) for protein tertiary structure prediction. PFF01 is based on physical interactions and was parameterized using experimental structures of a family of proteins believed to span a wide variety of possible folds. It contains empirical, although sequence-independent terms for hydrogen bonding. Its solvent-accessible surface area solvent model was first fit to transfer energies of small peptides. The parameters of the solvent model were then further optimized to stabilize the native structure of a single protein, the autonomously folding villin headpiece, against competing low-energy decoys. Here we validate the force field for five nonhomologous helical proteins with 20-60 amino acids. For each protein, decoys with 2-3 A backbone root mean-square deviation and correct experimental Cbeta-Cbeta distance constraints emerge as those with the lowest energy.

Algorithms↗
PubMed2006

Network analysis of the protein chain tertiary structures of heterocomplexes.

In this paper, the tertiary structures of protein chains of heterocomplexes were mapped to 2D networks; based on the mapping approach, statistical properties of these networks were systematically studied. Firstly, our experimental results confirmed that the networks derived from protein structures possess small-world properties. Secondly, an interesting relationship between network average degree and the network size was discovered, which was quantified as an empirical function enabling us to estimate the number of residue contacts of the protein chains accurately. Thirdly, by analyzing the average clustering coefficient for nodes having the same degree in the network, it was found that the architectures of the networks and protein structures analyzed are hierarchically organized. Finally, network motifs were detected in the networks which are believed to determine the family or superfamily the networks belong to. The study of protein structures with the new perspective might shed some light on understanding the underlying laws of evolution, function and structures of proteins, and therefore would be complementary to other currently existing methods.

Models, Molecular↗
PubMed1984

Change in the protein tertiary structure with non-enzymatic glycosylation of calf alpha-crystallin.

Non-enzymatic glycosylation of calf alpha-crystallin was induced by incubation with glucose. Glycosylated and non-glycosylated proteins were separated by affinity chromatography on Glyco Gel B boronic acid and were studied by circular dichroism (CD) and fluorescence. CD indicated that the glycosylated protein secondary structure was not altered, but the tertiary structure did undergo some changes. The CD band of this protein between 290 and 310 nm decreased in intensity. Extrinsic fluorescence probes, TNS (6-(p-toluidinyl) naphthalene-2-sulfonate) and MIANS (6-(4'-maleimidyl-anilino) naphthalene-2-sulfonic acid), indicated changes in both TNS binding sites and the sulfhydryl groups to a less hydrophobic microenvironment. Our results suggest that the glycosylation of protein leads to partial unfolding, and facilitates the sulfhydryl to oxidation.

Animals↗