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PubMed2006

Localization of binding sites in protein structures by optimization of a composite scoring function.

The rise in the number of functionally uncharacterized protein structures is increasing the demand for structure-based methods for functional annotation. Here, we describe a method for predicting the location of a binding site of a given type on a target protein structure. The method begins by constructing a scoring function, followed by a Monte Carlo optimization, to find a good scoring patch on the protein surface. The scoring function is a weighted linear combination of the z-scores of various properties of protein structure and sequence, including amino acid residue conservation, compactness, protrusion, convexity, rigidity, hydrophobicity, and charge density; the weights are calculated from a set of previously identified instances of the binding-site type on known protein structures. The scoring function can easily incorporate different types of information useful in localization, thus increasing the applicability and accuracy of the approach. To test the method, 1008 known protein structures were split into 20 different groups according to the type of the bound ligand. For nonsugar ligands, such as various nucleotides, binding sites were correctly identified in 55%-73% of the cases. The method is completely automated (http://salilab.org/patcher) and can be applied on a large scale in a structural genomics setting.

Amino Acid Sequence↗

PubMed2005

Potential functions for hydrogen bonds in protein structure prediction and design.

Hydrogen bonds are an important contributor to free energies of biological macromolecules and macromolecular complexes, and hence an accurate description of these interactions is important for progress in biomolecular modeling. A simple description of the hydrogen bond is based on an electrostatic dipole-dipole interaction involving hydrogen-donor and acceptor-acceptor base dipoles, but the physical nature of hydrogen bond formation is more complex. At the most fundamental level, hydrogen bonding is a quantum mechanical phenomenon with contributions from covalent effects, polarization, and charge transfer. Recent experiments and theoretical calculations suggest that both electrostatic and covalent components determine the properties of hydrogen bonds. Likely, the level of rigor required to describe hydrogen bonding will depend on the problem posed. Current approaches to modeling hydrogen bonds include knowledge-based descriptions based on surveys of hydrogen bond geometries in structural databases of proteins and small molecules, empirical molecular mechanics models, and quantum mechanics-based electronic structure calculations. Ab initio calculations of hydrogen bonding energies and geometries accurately reproduce energy landscapes obtained from the distributions of hydrogen bond geometries observed in protein structures. Orientation-dependent hydrogen bonding potentials were found to improve the quality of protein structure prediction and refinement, protein-protein docking, and protein design.

Hydrogen↗

PubMed1977

Gel electrophoretic analysis of structural proteins of the normal canine and human hearts.

1. Gel electrophoretic analysis of structural proteins extracted from myocardial tissues in the presence of sodium dodecylsulfate (SDS) is applicable to study the relative amount of structural proteins from less than 1 Gm of heart tissue. 2. The compositions of structural proteins of the right and left atria and ventricles of the normal canine heart were identical and similar to those of skeletal muscle. 3. The compositions of structural proteins of the atrium and ventricle of the normal human heart were also identical.

Actinin↗

PubMed2005

A tree-decomposition approach to protein structure prediction.

This paper proposes a tree decomposition of protein structures, which can be used to efficiently solve two key subproblems of protein structure prediction: protein threading for backbone prediction and protein side-chain prediction. To develop a unified tree-decomposition based approach to these two subproblems, we model them as a geometric neighborhood graph labeling problem. Theoretically, we can have a low-degree polynomial time algorithm to decompose a geometric neighborhood graph G = (V, E) into components with size O(|V|((2/3))log|V|). The computational complexity of the tree-decomposition based graph labeling algorithms is O(|V|Delta(tw+1)) where Delta is the average number of possible labels for each vertex and tw( = O(|V|((2/3))log|V|)) the tree width of G. Empirically, tw is very small and the tree-decomposition method can solve these two problems very efficiently. This paper also compares the computational efficiency of the tree-decomposition approach with the linear programming approach to these two problems and identifies the condition under which the tree-decomposition approach is more efficient than the linear programming approach. Experimental result indicates that the tree-decomposition approach is more efficient most of the time.

Algorithms↗

PubMed2005

New York-Structural GenomiX Research Consortium (NYSGXRC): a large scale center for the protein structure initiative.

Structural GenomiX, Inc. (SGX), four New York area institutions, and two University of California schools have formed the New York Structural GenomiX Research Consortium (NYSGXRC), an industrial/academic Research Consortium that exploits individual core competencies to support all aspects of the NIH-NIGMS funded Protein Structure Initiative (PSI), including protein family classification and target selection, generation of protein for biophysical analyses, sample preparation for structural studies, structure determination and analyses, and dissemination of results. At the end of the PSI Pilot Study Phase (PSI-1), the NYSGXRC will be capable of producing 100-200 experimentally determined protein structures annually. All Consortium activities can be scaled to increase production capacity significantly during the Production Phase of the PSI (PSI-2). The Consortium utilizes both centralized and de-centralized production teams with clearly defined deliverables and hand-off procedures that are supported by a web-based target/sample tracking system (SGX Laboratory Information Data Management System, LIMS, and NYSGXRC Internal Consortium Experimental Database, ICE-DB). Consortium management is provided by an Executive Committee, which is composed of the PI and all Co-PIs. Progress to date is tracked on a publicly available Consortium web site (http://www.nysgxrc.org) and all DNA/protein reagents and experimental protocols are distributed freely from the New York City Area institutions. In addition to meeting the requirements of the Pilot Study Phase and preparing for the Production Phase of the PSI, the NYSGXRC aims to develop modular technologies that are transferable to structural biology laboratories in both academe and industry. The NYSGXRC PI and Co-PIs intend the PSI to have a transforming effect on the disciplines of X-ray crystallography and NMR spectroscopy of biological macromolecules. Working with other PSI-funded Centers, the NYSGXRC seeks to create the structural biology laboratory of the future. Herein, we present an overview of the organization of the NYSGXRC and describe progress toward development of a high-throughput Gene-->Structure platform. An analysis of current and projected consortium metrics reflects progress to date and delineates opportunities for further technology development.

Cloning, Molecular↗

PubMed1996

Two-dimensional gel analysis of [35S]methionine labelled and phosphorylated proteins present in virions and light particles of herpes simplex virus type 1, and detection of potentially new structural proteins.

Cells infected with herpes simplex virus (HSV) synthesize both infectious viruses and non-infectious light particles (L-particles). The latter contain the envelope and tegument components of the virions, but lack virus capsid and DNA. Electrophoresis in SDS-polyacrylamide gels (SDS-PAGE) has been used extensively for analysis of structural proteins in virions and L-particles. Two-dimensional (2-D) gel electrophoresis, however has a markedly higher resolution, and in the present work we have used this technique to study both [35S]methionine labelled and phosphorylated structural proteins in virions and L-particles. Proteins were assigned to the tegument or the envelope by the analysis of L-particles. Localization of structural proteins was also determined by stepwise solubilization in the presence of the neutral detergent NP-40 and NaCl, and by isolation of capsids from nuclei of infected cells. Different steps in posttranslational modification can be detected by 2-D gel electrophoresis such that a single polypeptide may appear as several spots. This was most clearly observed for some of the HSV-encoded glycoproteins which were shown to exist in multiple forms in the virion. Some polypeptides apparently not identified previously were either capsid associated, or localized in the tegument or envelope. The degrees of phosphorylation in L-particles and virions are almost identical for some proteins, but markedly different for others. Thus, glycoprotein E of HSV-1 is for the first time shown to be phosphorylated, and most heavily so in virions. The IE VMW)110 protein represents a group of proteins which are more phosphorylated in L-particles than in virions. Attempts are made to correlate the proteins detected by 2-D analysis with those previously separated by SDS-PAGE.

Animals↗

PubMed1989

Analyses of the terminal sequences of West Nile virus structural proteins and of the in vitro translation of these proteins allow the proposal of a complete scheme of the proteolytic cleavages involved in their synthesis.

The proteolytic processes involved in the synthesis of the structural proteins of the West Nile (WN) flavivirus were analyzed: The carboxy-terminal sequences of the structural proteins were determined and the proteins translated in vitro in the presence of membranes from a mRNA coding for the structural polyprotein were analyzed. The results obtained indicate that the following proteolytic activities are involved in the synthesis and assembly of WN virus structural proteins: The growing peptide chain which contains the sequences of the structural proteins in the order C-pre-M-E is cleaved at three places by cellular signalase(s). This cleavage generates the primary amino acid sequence of the mature structural proteins pre-M and E (and the amino-terminus of the ensuing nonstructural protein NS 1). The amino-terminal part of the polyprotein containing the amino acid residues 1 to 123 is released as a molecule which migrates slightly slower than the mature viral core protein and which presumably is associated to the RER membranes via its carboxy-terminal sequence. This protein is called the anchored C virus particles the anchored C protein is converted into mature C protein by removal of the carboxy-terminal hydrophobic segment containing the amino acid residues 106 to 123. Presumably a virus-coded protease which can cleave the polyprotein after two basic amino acid residues is responsible for this cleavage. The cell-associated WN virus particles are constructed from the proteins C, pre-M, and E which contain the amino residues 1-105, 124-290, and 291-787 of the polyprotein, respectively. Cleavage of the pre-M protein between amino acid residues 215 and 216, presumably by a cellular enzyme located in the Golgi vesicles, and loss of the amino-terminal fragment of this protein are associated with the release of virus from the cells.

Amino Acid Sequence↗

PubMed2003

Protein structure prediction via combinatorial assembly of sub-structural units.

Following the hierarchical nature of protein folding, we propose a three-stage scheme for the prediction of a protein structure from its sequence. First, the sequence is cut to fragments that are each assigned a structure. Second, the assigned structures are combinatorially assembled to form the overall 3D organization. Third, highly ranked predicted arrangements are completed and refined. This work focuses on the second stage of this scheme: the combinatorial assembly. We present CombDock, a combinatorial docking algorithm. CombDock gets an ordered set of protein sub-structures and predicts the inter-contacts that define their overall organization. We reduce the combinatorial assembly to a graph-theory problem, and give a heuristic polynomial solution to this computationally hard problem. We applied CombDock to various examples of structural units of two types: protein domains and building blocks, which are relatively stable sub-structures of domains. Moreover, we tested CombDock using increasingly distorted input, where the native structural units were replaced by similarly folded units extracted from homologous proteins and, in the more difficult cases, from globally unrelated proteins. The algorithm is robust, showing low sensitivity to input distortion. This suggests that CombDock is a useful tool in protein structure prediction that may be applied to large target proteins.

Algorithms↗

PubMed1981

Regional changes in cardiac structural proteins in myocardial infarction: biochemical and histologic correlates.

1. Quantitative analysis of structural proteins from a minute amount of myocardial tissue was performed from 10 mu thick cardiac tissue slices weighing 2 to 5 mg by the extraction in glycerol solution and by sodium dodecylsulfate (SDS) gel electrophoresis, and these changes were compared with the histologic alterations in the striated structure of the adjacent cardiac slices in the experimental myocardial infarction in the dog. 2. Approximately 69 micrograms of structural proteins were obtained from 1 mg of the normal heart muscle. In the central portions of the myocardial infarction, reductions in myosin heavy chain (HC), light chain (LC) 1 and alpha-actinin were observed at 12 to 24 hours after the coronary occlusion followed by the decrease in myosin LC 2 at 48 hours. Those changes became intense at 72 hours to 7 days, but restored gradually at 14 to 28 days. 3. Alterations in the striated structure of cardiac muscle fibers of the adjacent tissues slices were found simultaneously with the changes in structural proteins. At 12 to 24 hours after the coronary ligation increase in eosinophilia and overstretch of cross-striation were observed. The findings of coagulation necrosis, loss of striation, fragmentation, swelling of A-band, etc. of the infarcted fibers were markedly observed at 48 hours to 7 days, but the histologic restoration of cardiac fibers was found with the recovery of the infarcted tissue at 14 to 28 days after the coronary ligation. 4. Changes in the compositions of structural proteins corresponded well to the alterations in the striated structure in chronology and in quantity.

Actinin↗

PubMed1996

Induction of antibodies against structural proteins of hepatitis C virus in mice using recombinant adenovirus.

Replication-deficient recombinant adenoviruses expressing structural proteins of hepatitis C virus (HCV) were constructed. Each recombinant lacks adenoviral E1A and E3 genes and bears expression units for HCV structural proteins. The expression units contain HCV cDNAs coding for either the protein or core, one of two envelopes (E1 and E2) or all of these structural proteins (core, E1 and E2) under the control of the SR alpha promoter. In HeLa or HepG2 cells, the recombinants can express efficiently HCV genes after infection without replication of the recombinants. We detected 22-kDa core, 35-kDa E1 and 58-kDa E2 proteins of HCV in these cells. The recombinant expressing all three HCV structural proteins was inoculated into mice. Antibodies to each of the three HCV proteins were detected in all of the ten mice tested. The results indicate that the recombinant adenoviruses efficiently express HCV genes and induce specific antibody against the expressed HCV proteins in animals.

Adenoviridae↗

PubMed2003

Role of the asialoglycoprotein receptor in binding and entry of hepatitis C virus structural proteins in cultured human hepatocytes.

We used a baculovirus-based system to prepare structural proteins of hepatitis C virus (HCV) genotype 1a. Binding of this preparation to cultured human hepatic cells was both dose dependent and saturable. This binding was decreased by calcium depletion and was partially prevented by ligands of the asialoglycoprotein receptor (ASGP-R), thyroglobulin, asialothyroglobulin, and antibody against a peptide in the carbohydrate recognition domain of ASGP-R but not preimmune antibody. Uptake by hepatocytes was observed with both radiolabeled and dye-labeled HCV structural proteins. With hepatocytes expressing the hH1 subunit of the ASGP-R fused to green fluorescent protein, we could show by confocal microscopy that dye stain cointernalized with the fusion protein in an area surrounding the nucleus. Internalization was more efficient with a preparation containing p7 than with one that did not. The two preparations bound to transfected 3T3-L1 cells expressing either both (hH1 and hH2) subunits of the ASGP-R (3T3-22Z cells) or both hH1 and a functionally defective variant of hH2 (3T3-24X cells) but not to parental cells. Additionally, uptake of dye-labeled preparation containing p7 was observed with 3T3-22Z cells but not with 3T3-L1 or 3T3-24X cells or with the preparation lacking p7, suggesting that p7 regulates the internalization properties of HCV structural proteins. Our observations suggest that HCV structural proteins bind to and cointernalize with the ASGP-R in cultured human hepatocytes.

3T3 Cells↗

PubMed1978

Prediction of protein structure from amino acid sequence.

In principle, it is possible to predict theoretically the three-dimensional structure of a protein from its amino acid sequence. Recently substantial progress towards this goal has been made by the use of simple models to represent protein conformation and interatomic interactions, together with the knowledge gained form analyses of know protein structures.

Amino Acid Sequence↗

PubMed2001

Modeling of the structural features of integral-membrane proteins reverse-environment prediction of integral membrane protein structure (REPIMPS).

The Profiles-3D application, an inverse-folding methodology appropriate for water-soluble proteins, has been modified to allow the determination of structural properties of integral-membrane proteins (IMPs) and for testing the validity of solved and model structures of IMPs. The modification, known as reverse-environment prediction of integral membrane protein structure (REPIMPS), takes into account the fact that exposed areas of side chains for many residues in IMPs are in contact with lipid and not the aqueous phase. This (1) allows lipid-exposed residues to be classified into the correct physicochemical environment class, (2) significantly improves compatibility scores for IMPs whose structures have been solved, and (3) reduces the possibility of rejecting a three-dimensional structure for an IMP because the presence of lipid was not included. Validation tests of REPIMPS showed that it (1) can locate the transmembrane domain of IMPs with single transmembrane helices more frequently than a range of other methodologies, (2) can rotationally orient transmembrane helices with respect to the lipid environment and surrounding helices in IMPs with multiple transmembrane helices, and (3) has the potential to accurately locate transmembrane domains in IMPs with multiple transmembrane helices. We conclude that correcting for the presence of the lipid environment surrounding the transmembrane segments of IMPs is an essential step for reasonable modeling and verification of the three-dimensional structures of these proteins.

Bacteriorhodopsins↗

PubMed1980

Turnover rates and synthesis of cardiac structural proteins in normal and hypertrophied heart.

Turnover rates and synthesis of cardiac structural proteins were studied in normal and hypertrophied rabbit heart. The order of incorporation rates of radioactive lysine in normal heart was: left ventricular greater than right ventricular greater than atrial greater than skeletal myosin B. In left ventricular muscle, the order of relative turnover rates of structural proteins was: native tropomyosin greater than the complex of 10 S-actinin and alpha-actinin greater than myosin heavy chain greater than myosin light chain greater than (soluble protein) greater than actin. After aortic constriction (to three-fourths of its original circumference), the rates of incorporation of radioactive lysine into each structural protein fraction increased, reaching a peak on the 7th day. The values returned to the levels of the normal group after 1 month. It was noted that the increase of incorporation into native tropomyosin was greater than the other structural proteins 7 days after constriction.

Actinin↗

PubMed1993

Heterocomplexes of tick-borne encephalitis structural and non-structural proteins.

The existence of the complex of structural and non-structural proteins in the tick-borne encephalitis (TBE) virus is shown. The complex was isolated from virus-containing cultural medium by immunoaffinity chromatography on monoclonal antibodies (MAbs). By enzyme immunoassay and immunoblotting with the use of appropriate MAbs it was demonstrated that this complex consists of structural (protein E), and non-structural (NS1) glycoproteins. Also, the trimer E-NS1-NS3 can be isolated. It is proposed that this trimer is the viral replicative complex.

Antibodies, Monoclonal↗

PubMed1984

Structural proteins of Chikungunya virus.

Polyacrylamide gel analysis of the structural proteins of African and Asian strains of Chikungunya virus, an alphavirus, showed that both strains contain three structural proteins: glycosylated E1 and E2, embedded in the viral envelope, and a nonglycosylated nucleocapsid protein. In pulse-chase experiments the precursor protein PE2 was chased into glycoprotein E2, which migrated slightly faster than did glycoprotein E1. The third Chikungunya glycoprotein, E3, was not associated with mature virions but was released into culture fluids. With glycoproteins E1 and E2, separated by glass wool column chromatography, it was shown that hemagglutinating activity is associated with glycoprotein E1.

Chikungunya virus↗

PubMed2003

On the rotational operators in protein structure simulations.

The reduction of the computational complexity of the algorithms dealing with protein structure analysis and conformation predictions is of prime importance. One common element in most of these algorithms is the process of transforming geometrical information between dihedral angles and Cartesian coordinates of the atoms in the protein using rotational operators. In the literature, the operators used in protein structures are rotation matrices, quaternions in vector and matrix forms and the Rodrigues-Gibbs formula. In the protein structure-related literature, the most widely promoted rotational operator is the quaternions operator. In this work, we studied the computational efficiency of the mathematical operations of the above rotational operators applied to protein structures. A similar study applied to protein structures has not been reported previously. We concluded that the computational efficiency of these rotational operators applied to protein chains is different from those reported for other applications (such as mechanical machinery) and the conclusions are not analogous. Rotation matrices are the most efficient mathematical operators in the protein chains. We examined our findings in two protein molecules: Ab1 tyrosine kinase and heparin-binding growth factor 2. We found that the rotation matrix operator has between 2 and 187% fewer mathematical operations than the other rotational operators.

Computer Simulation↗

PubMed1984

Subcellular distribution of viral structural proteins during simian virus 40 infection.

The amounts of simian virus 40 structural polypeptides Vp1, Vp2, and Vp3 in different subcellular fractions at various times after lytic infection were determined by a quantitative immunoblotting procedure. Simian virus 40-infected cells were lysed with a buffer containing Nonidet P-40 to yield a soluble fraction. The Nonidet P-40-insoluble fraction was further fractionated in the presence of deoxycholate and Tween 40 to yield a soluble fraction (cytoskeletal) and an insoluble fraction (Nuc), which is primarily cell nuclei. At 33 h postinfection, the majority of viral structural proteins was found in the cell nucleus, whereas, at 48 to 65 h postinfection, Vp1 was distributed evenly among all cell fractions and Vp2 and Vp3 were found predominantly in the cytoskeletal and Nuc fractions. Thus, not all of the viral polypeptides synthesized in the cytoplasm migrated into the cell nucleus. Throughout infection, the molar ratio (Vp3/Vp2) was rather constant in all subcellular fractions, indicating that the synthesis or processing or both of Vp2 and Vp3 are coordinately regulated. The molar ratio of Vp1/(Vp2 + Vp3) varied among the fractions. The Vp1/(Vp2 + Vp3) molar ratio in the soluble fraction varied during the course of infection; however, constant ratios were maintained in the cytoskeletal and Nuc fractions. Thus, the mechanism which controls the movement of Vp1 to different compartments of the cell appears to be different from that of Vp2 and Vp3. The Vp1/(Vp2 + Vp3) value in the Nuc fraction was similar to the ratio found in virus particles. The constant molar distribution of Vp1, Vp2, and Vp3 in the Nuc fraction throughout infection suggests that there is a specific mechanism which regulates the transport of viral structural proteins. These results support the hypothesis that the structural proteins of simian virus 40 are transported into the cell nucleus in precise proportions.

Animals↗