SEARCH · PubMed Health

Results for “Homology modelling”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed1995

A self consistent mean field approach to simultaneous gap closure and side-chain positioning in homology modelling.

A new computational procedure which simultaneously provides gap closure and side-chain positioning in homology modelling is described. It uses a database search scheme to generate fragments to model gaps, a rotamer library to define side-chain conformations, and iteratively refines a conformational matrix CM, such that its elements CM(i,j,o) and CM(i,j,k) give the probabilities that the backbone of residue i adopts the conformation described by fragment j and that its side-chain adopts the conformation of its possible rotamer k. Each residue experiences the average of all possible environments, weighted by their respective probabilities. The method converges, thereby deserving the name of 'self consistent mean field' approach.

Algorithms↗

PubMed1992

Homology modelling of integrin EF-hands. Evidence for widespread use of a conserved cation-binding site.

Integrin alpha-subunits contain three or four peptide sequences that are similar to the EF-hand, a 13-residue bivalent cation-binding motif found in calmodulin and parvalbumin. The integrin sequences differ from classical EF-hands in that they lack a co-ordinating residue at position 12. One hypothesis to explain integrin-ligand binding is that aspartate-containing recognition sequences in integrin ligands, which bind at or near to the EF-hand-like sequences, may take the place of the missing residue and co-ordinate directly to the bound cation. In this report, homology modelling of integrin EF-hand-like sequences has been performed using the X-ray structure of calmodulin as a template in order to assess the functional activity of the integrin sequences. In the calmodulin-integrin hybrid structures, integrin EF-hand-like sequences were able to retain cations whereas control sequences did not. Structural analyses demonstrated that the integrin sequences in the hybrid proteins closely resembled conventional EF-hands. The integrin sequences are therefore highly likely to bind Ca2+ ions in vivo, a prerequisite for the ligand-binding model. Database searching with a matrix derived from known integrin EF-hand-like sequences has been used to identify other proteins containing the integrin EF-hand-like motif. Annexin V (anchorin CII), atrial natriuretic peptide receptors and the 70 kDa heat-shock protein were identified by the matrix; the functions of these proteins are known from previous studies to be bivalent cation-dependent. These findings suggest that the integrin EF-hand-like sequence may be a more common motif than originally thought.

Amino Acid Sequence↗

PubMed1992

Homology model of thyroxine binding globulin and elucidation of the thyroid hormone binding site.

The tertiary structure of thyroxine binding globulin (TBG) has been modelled on the basis of its close homology to alpha 1-antitrypsin, the archetype of the serine protease inhibitor (serpin) superfamily. Energy minimization was applied to the model to refine the structure further. The putative thyroid hormone binding region suggested in previous labelling studies was found to exist within a beta-barrel structure of complementary dimensions to the thyroid hormones. The model also revealed that the binding cleft provides the hydrophobic environment and specific ionic interaction sites deemed important for thyroid hormone binding. The model is in good agreement with evidence derived from previously reported T3 and T4 binding, stability and isoelectric focussing studies of TBG and TBG variants. Finally, T4 analogue and drug binding studies have enabled us to postulate the orientation and manner of hormone binding to TBG. This may prove to be of assistance in the development of potent and specific, non-thyroidal ligands and also aid in the understanding of physiological thyroid hormone binding interactions.

Amino Acid Sequence↗

PubMed2024

Modeling homologous chromosome recognition via nonspecific interactions.

In many organisms, most notably Drosophila, homologous chromosomes associate in somatic cells, a phenomenon known as somatic pairing, which takes place without double strand breaks or strand invasion, thus requiring some other mechanism for homologs to recognize each other. Several studies have suggested a "specific button" model, in which a series of distinct regions in the genome, known as buttons, can associate with each other, mediated by different proteins that bind to these different regions. Here, we use computational modeling to evaluate an alternative "button barcode" model, in which there is only one type of recognition site or adhesion button, present in many copies in the genome, each of which can associate with any of the others with equal affinity. In this model, buttons are nonuniformly distributed, such that alignment of a chromosome with its correct homolog, compared with a nonhomolog, is energetically favored; since to achieve nonhomologous alignment, chromosomes would be required to mechanically deform in order to bring their buttons into mutual register. By simulating randomly generated nonuniform button distributions, many highly effective button barcodes can be easily found, some of which achieve virtually perfect pairing fidelity. This model is consistent with existing literature on the effect of translocations of different sizes on homolog pairing. We conclude that a button barcode model can attain highly specific homolog recognition, comparable to that seen in actual cells undergoing somatic homolog pairing, without the need for specific interactions. This model may have implications for how meiotic pairing is achieved.

Animals↗

PubMed1992

Solution structure of neuronal bungarotoxin determined by two-dimensional NMR spectroscopy: calculation of tertiary structure using systematic homologous model building, dynamical simulated annealing, and restrained molecular dynamics.

Neuronal bungarotoxin has previously been shown, using two-dimensional 1H NMR spectroscopy, to have a triple-stranded antiparallel beta-sheet structure which dimerizes in solution [Oswald, R.E., Sutcliffe, M.J., Bamberger, M., Loring, R.H., Braswell, E., & Dobson, C.M. (1991) Biochemistry 30, 4901-4909]. In this paper, structural calculations are described which use the 582 experimentally measured NOE restraints in conjunction with 27 phi-angle restraints from J-value measurements. The positions of the N-terminal region and C-terminal region were poorly defined in the calculated structures with respect to the remainder of the structure. The region of the structure containing the triple-stranded beta-sheet was, however, well defined and similar to that found in the structure of homologous alpha-bungarotoxin (45% amino acid identity). The experimental restraints did not result in a well-defined dimer interface region because of the small number of NOEs which could be identified in this region. An approach was therefore adopted which produced model structures based to varying degrees on the alpha-bungarotoxin structure. Fourteen different structures were generated in this manner and subsequently used as starting points for refinement using dynamical simulated annealing followed by restrained molecular dynamics. This approach, which combines NMR data and homologous model building, has enabled a family of structures to be proposed for the dimeric molecule. In particular, Phe49 has been identified as possibly playing an important role in dimer formation, this residue in one chain interacting with the corresponding residue in the adjacent chain.

Amino Acid Sequence↗

PubMed1992

Homology modeling of a heme protein, lignin peroxidase, from the crystal structure of cytochrome c peroxidase.

A 3-dimensional model of lignin peroxidase (LiP) was constructed based on its sequence homology with other peroxidases, particularly cytochrome c peroxidase, the only protein with a known crystal structure in the peroxidase family. The construction of initial conformations of insertions and deletions was assisted by secondary structure predictions, amphipathic helix predictions, and consideration of the specific protein environment. A succession of molecular dynamics simulations of these regions with surrounding residues as constraints were carried out to relax the bond lengths and angles. Full protein molecular dynamics simulations with explicit consideration of bound waters were performed to relax the geometry and to identify dynamically flexible regions of the successive models for further refinement. Among the important functionally relevant structural features predicted are: (i) four disulfide bonds are predicted to be formed between Cys3 and Cys15, Cys14 and Cys285, Cys34 and Cys120 and Cys249 and Cys317; (ii) a glycosylation site, Asn257, was located on the surface; (iii) Glu40 was predicted to form a salt bridge with Arg43 on the distal side of the heme and was considered as a possible origin for the pH dependence of compound I formation; and (iv) two candidate substrate binding sites with a cluster of surface aromatic residues and flexible backbones were found in the refined model, consistent with the nature of known substrates of LiP. Based on these predicted structural features of the model, further theoretical and experimental studies are proposed to continue to elucidate the structure and function of LiP.

Amino Acid Sequence↗

PubMed1989

Construction of side-chains in homology modelling. Application to the C-terminal lobe of rhizopuspepsin.

A detailed and rule-based side-chain modelling procedure for globular proteins is presented. It uses the conformational information contained in a homologous (template) structure as a starting point and includes recipes for atom placement and for checking and improving the atomic positions. The scheme does not rely on intuitive judgements or visual examination of the model during construction or refinement. It comprises four stages; the first three are relatively simple and the fourth is more complex. In the first stage, initial conformations for as many atoms as possible are transferred from the template structure based on the application of trends reported previously. Second, these trends are used to correct poor van der Waals overlaps. Third, the remaining side-chains atoms (those for which no information is contained in the template) are placed by evaluating their rigid rotation, van der Waals surfaces. The fourth stage consists of a hierarchial series of conformational checks. They involve the evaluation of individual residue energies in the absence and presence of the rest of the protein relative to statistical trends observed in the template structure, the comparison of hydrogen-bonding patterns and side-chain accessibilities in the model and template and brief energy minimization followed by an evaluation of the rigid rotation potential energy surfaces of each side-chain. The checks pinpoint "incorrectly" modelled side-chains, suggest conformational changes and provide a means for determining the portions of the model that are likely to be correct and those likely to be in error. The procedure developed in the paper is tested by modelling the side-chains of the C-terminal lobe of the aspartyl proteinase rhizopuspepsin, using the rhizopuspepsin backbone and the homologous protein, penicillopepsin, as a template for the side-chains. The resultant model was compared to the high-resolution X-ray structure of rhizopuspepsin. Using penicillopepsin data only (stage I), 58% of the chi 1 dihedrals and 44% of the chi 2 dihedrals were modelled correctly. Once poor van der Waals overlaps had been corrected and all of the atoms had been placed (stages II and III), 86% of the chi 1 dihedrals and 75% of the chi 2 dihedrals were correct. After the refinement had been completed (stage IV), 92% of the chi 1 dihedrals and 81% of the chi 2 dihedrals were correctly positioned.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

PubMed1995

Proposed structure of the A domains of factor VIII by homology modelling.

We have predicted a structure for the three A domains of blood coagulation factor VIII by virtue of their homology to blue copper-binding proteins. This structure, consisting of six beta-barrels, is arranged in a triangular configuration with a single type II copper-binding site linking the A1 and A3 domains.

Amino Acid Sequence↗

PubMed1995

X-ray absorption studies and homology modeling define the structural features that specify the nature of the copper site in rusticyanin.

Rusticyanin, a blue copper protein, possessing the highest redox potential among this class of proteins and a high stability at acidic pH reveals homology with the C-terminal end of the other single copper containing blue proteins and an interesting homology to parts of the blue copper domain of the multi-copper proteins such as the nitrite reductases. Extended X-ray absorption fine structure (EXAFS) data at pH 2.0 reveal that Cu is ligated to two His and a Cys in the inner coordination sphere, similar to other blue copper centers. Modeling studies suggest that His85 is the ligating histidine from the N-terminal end. Its neighboring residue is a serine rather than the asparagine found in all known blue Cu proteins. The high stability of the copper site may arise in part due to this substitution. The Cu binding site is surrounded by aromatic residues which may provide further protection for the metal in an acidic environment. In addition, the high number of solvent-exposed uncompensated lysine residues is likely to be of functional relevance under low pH conditions. EXAFS data show a very small change (relative to azurin) in the copper site upon reduction, consistent with a more constrained copper center in rusticyanin compared to azurin and a higher redox potential.

Absorptiometry, Photon↗

PubMed1994

Homology modelling and 1H NMR studies of human leukaemia inhibitory factor.

Human leukaemia inhibitory factor (LIF) is a glycoprotein with a diverse range of activities on many cell types. A molecular model of LIF has been constructed based mainly on the structure of the related cytokine granulocyte colony-stimulating factor, and refined using simulated annealing and molecular dynamics in water. The model was stable during molecular dynamics refinement and is consistent with known stereochemical data on proteins. It has been assessed by comparison with 1H NMR data on the ionization behaviour of the six histidine residues in LIF, the imidazolium pKa values of which range from 3.6 to 7.4. These pKa values were assigned to individual histidine residues from NMR studies on a series of His-->Ala mutants. The environments of the histidine residues in the model account very well for their observed ionization behaviour. Furthermore, the model is consistent with mutagenesis studies which have defined a group of amino acid residues involved in receptor binding.

Amino Acid Sequence↗

PubMed1990

Evaluation of homology modeling of HIV protease.

The model of human immunodeficiency virus (HIV-1) protease which was based on the crystal structure of Rous sarcoma virus (RSV) protease has been compared to the recently determined crystal structure of chemically synthesized HIV-1 protease. The overall difference between the model and crystal structure was 1.4 A root mean square (rms) deviation for 86 superimposed C alpha atoms. The position of the flexible flap differs in the model and six residues at the amino terminus were incorrectly placed. With these exceptions, all atoms of the model and crystal structure agree to 2.1 A rms deviation. The conformation of some surface bends in the model agrees less well with the crystal structure. Identical amino acids in RSV and HIV proteases were modeled more reliably than different types of amino acids. The amino acids which form the substrate binding site were modeled most accurately to 1.2 A rms deviation for all atoms compared to the crystal structure. This suggests that functionally significant regions of related proteins can be modeled with high accuracy. The model gave correct predictions for residues making interactions with the substrate, and therefore could be used to design inhibitors. The model based on the RSV protease structure is more similar to the experimental structure than are previous models based on the structures of non-viral aspartic proteases.

Amino Acid Sequence↗

PubMed1991

Homology modelling and protein engineering strategy of subtilases, the family of subtilisin-like serine proteinases.

Subtilases are members of the family of subtilisin-like serine proteases. Presently, greater than 50 subtilases are known, greater than 40 of which with their complete amino acid sequences. We have compared these sequences and the available three-dimensional structures (subtilisin BPN', subtilisin Carlsberg, thermitase and proteinase K). The mature enzymes contain up to 1775 residues, with N-terminal catalytic domains ranging from 268 to 511 residues, and signal and/or activation-peptides ranging from 27 to 280 residues. Several members contain C-terminal extensions, relative to the subtilisins, which display additional properties such as sequence repeats, processing sites and membrane anchor segments. Multiple sequence alignment of the N-terminal catalytic domains allows the definition of two main classes of subtilases. A structurally conserved framework of 191 core residues has been defined from a comparison of the four known three-dimensional structures. Eighteen of these core residues are highly conserved, nine of which are glycines. While the alpha-helix and beta-sheet secondary structure elements show considerable sequence homology, this is less so for peptide loops that connect the core secondary structure elements. These loops can vary in length by greater than 150 residues. While the core three-dimensional structure is conserved, insertions and deletions are preferentially confined to surface loops. From the known three-dimensional structures various predictions are made for the other subtilases concerning essential conserved residues, allowable amino acid substitutions, disulphide bonds, Ca(2+)-binding sites, substrate-binding site residues, ionic and aromatic interactions, proteolytically susceptible surface loops, etc. These predictions form a basis for protein engineering of members of the subtilase family, for which no three-dimensional structure is known.

Amino Acid Sequence↗

PubMed1995

Homology model of human interferon-alpha 8 and its receptor complex.

Human interferon-alpha 8 (HuIFN alpha 8), a type I interferon (IFN), is a cytokine belonging to the hematopoietic super-family that includes human growth hormone (HGH). Recent data identified two human type I IFN receptor components. One component (p40) was purified from human urine by its ability to bind to immobilized type I IFN. A second receptor component (IFNAR), consisting of two cytokine receptor-like domains (D200 and D200'), was identified by expression cloning. Murine cells transfected with a gene encoding this protein were able to produce an antiviral response to human IFN alpha 8. Both of these receptor proteins have been identified as members of the immunoglobulin superfamily of which HGH receptor is a member. The cytokine receptor-like structural motifs present in p40 and IFNAR were modeled based on the HGH receptor X-ray structure. Models of the complexes of HuIFN alpha 8 with the receptor subunits were built by superpositioning the conserved C alpha backbone of the HuIFN alpha 8 and receptor subunit models with HGH and its receptor complex. The HuIFN alpha 8 model was constructed from the C alpha coordinates of murine interferon-beta crystal structure. Electrostatic potentials and hydrophobic interactions appear to favor the model of HuIFN alpha 8 interacting with p40 at site 1 and the D200' domain of IFNAR at site 2 because there are regions of complementary electrostatic potential and hydrophobic interactions at both of the proposed binding interfaces. Some of the predicted receptor binding residues within HuIFN alpha 8 correspond to functionally important residues determined previously for human IFN alpha 1, IFN alpha 2, and IFN alpha 4 subtypes by site-directed mutagenesis studies. The models predict regions of interaction between HuIFN alpha 8 and each of the receptor proteins, and provide insights into interactions between other type I IFNs (IFN-alpha subtypes and IFN-beta) and their respective receptor components.

Amino Acid Sequence↗

PubMed1986

Using known substructures in protein model building and crystallography.

Retinol binding protein can be constructed from a small number of large substructures taken from three unrelated proteins. The known structures are treated as a knowledge base from which one extracts information to be used in molecular modelling when lacking true atomic resolution. This includes the interpretation of electron density maps and modelling homologous proteins. Models can be built into maps more accurately and more quickly. This requires the use of a skeleton representation for the electron density which improves the determination of the initial chain tracing. Fragment-matching can be used to bridge gaps for inserted residues when modelling homologous proteins.

Models, Molecular↗

PubMed1991

The split-end model for homologous recombination at double-strand breaks and at Chi.

In recent years two different styles of model for homologous recombination have been discussed, depending on whether or not the recombination event occurs in the vicinity of a double-strand break in DNA. The models of Holliday and Meselson and Radding exemplify those that do not involve a break whereas the model of Szostak et al is taken as an example of those that do. Recent advances in understanding a prototypic recombination system thought to promote exchange distant from DNA ends, at Chi sites, suggest a mechanism of initiation neither like Holliday/Meselson-Radding nor like Szostak et al. In those models, only one strand of DNA may invade a homologous DNA molecule. We propose a model for Chi in which exonuclease degrades DNA from a double-strand break to the Chi site; the exonuclease is converted into a helicase upon interaction with Chi; unwinding produces a recombinagenic split-end, and both 3'- and 5'-ending strands at the split-end are capable of invading a homologue. Different genetic consequences are proposed to result from invasion by each. We review evidence supporting the split-end model and suggest its application in at least some cases previously considered to proceed via the Meselson/Radding model and by the double-strand-break repair model of Szostak et al.

DNA↗

PubMed1992

A mathematical model of homologous recombination in cultured cells.

This work presents a model describing the rate of recombination between homologous segments of DNA stably integrated into the genome of cultured cells. The model has been applied to rat cell lines carrying the polyomavirus middle T oncogene and a functional origin of viral DNA replication. Introduction of the gene coding for the polyoma large T antigen or the SV40 large T antigen into cells by DNA transfection promotes homologous recombination in the resident viral inserts with rates varying between 0.1 x 10(-3) and 3.7 x 10(-1) per cell generation.

Animals↗

PubMed1983

Temporary use of silicone oil in the treatment of proliferative vitreoretinopathy. An experimental study with a new animal model.

Homologous fibroblasts were injected into vitrectomized rabbit eyes. This injection produced a total retinal detachment in all ten eyes of a control series. In each case the detachment was due to the contraction of a membrane which had grown on the retinal surface as seen in human proliferative vitreoretinopathy (PVR). In another group of ten eyes, silicone oil was injected before the fibroblastic membrane contracted, and removed again a few weeks later. This temporary tamponade of silicone oil reduced the rate of detachment to 50%. Silicone oil did not prevent the preretinal membrane from growing but mechanically decreased its contraction.

Animals↗

PubMed1990

Modeling by homology of RNA binding domain in A1 hnRNP protein.

Eukaryotic nuclear RNA binding proteins share a common sequence motif thought to be implicated in RNA binding. One of the two domains present in A1 hnRNP protein, has been modelled by homology in order to make a prediction of the main features of the RNA binding site. Acylphosphatase (EC 3.6.1.7) was selected as template for the modeling experiment. The predicted RNA binding site is a beta-sheet containing the two RNP consensus sequences as well as lysines and arginines conserved among the family.

Acid Anhydride Hydrolases↗