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Biomedical subjects

A J Olson

Publications and source records attributed to A J Olson.

At least 55 records · Page 3Linked to original sources
PubMed1993

Approximation and characterization of molecular surfaces.

The representation and characterization of molecular surfaces are important in many areas of molecular modeling. Parametric representations of protein molecular surfaces are a compact way to describe a surface, and are useful for the evaluation of surface properties such as the normal vector, principal curvatures, and principal curvature directions. Simplified representations of molecular surfaces are useful for efficient rendering and for the display of large-scale surface features. Several techniques for representing surfaces by expansions of spherical harmonic functions have been reported, but these techniques require that the radius function is single valued, that is, each ray from an origin inside the surface intersects the surface at one and only one point. A new technique is described that removes this limitation and can be used to compute surface shape properties.

Chemical Phenomena↗
PubMed1993

Shape analysis of molecular surfaces.

The description of molecular shape is important in the analysis of protein-protein and protein-ligand interactions. We describe volumetric and surface-based techniques for computing shape properties of molecular surfaces. The surface is defined as an isocontour of an approximate electron density function. Each technique can compute several scalar and vector surface properties such as the Gaussian and mean curvature, principal curvatures, and principal curvature directions. Shape properties are derived from the eigenvalues and eigenvectors of a 3 by 3 matrix for each surface point. In the volumetric approach, the matrix is the second derivative of an approximate electron density function. In the surface-based approach, the matrix is the approximate gradient of the surface normal. Derivatives are computed by convolving the density or the surface normals with the derivatives of a Gaussian function. The variance of the Gaussian determines the effective length scale at which the surface is analyzed. Scalar surface properties are displayed as colored dots or shaded triangles, and vector properties are displayed as line segments from each surface point. This report describes the implementation of these procedures and their use in computing the shape properties of Cu-Zu superoxide dismutase.

Computer Simulation↗
PubMed1993

Automated docking in crystallography: analysis of the substrates of aconitase.

Automated docking of substrates to proteins of known structure aids the process of crystallographic analysis in two ways. First, automated docking can be used to generate a small number of starting models for substrates using only protein coordinates from an early stage of refinement. Second, automated docking provides a method for exploring aspects of catalysis that are inaccessible to crystallography by postulating binding modes of catalytic intermediates. This paper describes the use of automated docking to explore the binding of substrates to aconitase. The technique starts with a substrate molecule in an arbitrary configuration and position and finds favorable docked configurations in a (static) protein active site based on a molecular mechanics type force field. Using protein coordinates from an early stage of refinement of an aconitase-isocitrate complex, we successfully predicted the binding configuration of isocitrate. Four configurations were found, the energetically most favorable of which fit the observed electron density well and was used as a starting model for further refinement. Two configurations were found in citrate docking experiments, the second of which approximates the mode of substrate binding in an aconitase-nitrocitrate complex. We were also able to propose two binding modes of the catalytic intermediate cis-aconitate. These correspond closely to the isocitrate and the citrate binding modes. The relation of these new results to the proposed reaction mechanism is discussed.

Aconitate Hydratase↗
PubMed1993

Soluble proteins: size, shape and function.

Why are proteins so big? Why do cells build oligomeric proteins? A visual survey of the protein structures available in the Protein Data Bank sheds new light on these questions.

Proteins↗
PubMed1992

Molecular illustration in black and white.

Two-dimensional image processing techniques are used to create black and white illustrations from conventional z-buffer images. The illustrations appear to be composed of lines--outlines, contour lines, and hatched shading--but are calculated as grey-scale raster images. They have the advantage of faithful reproduction in publication and ease of display on workstations and laser printers. A FORTRAN source code is provided.

Computer Graphics↗
PubMed1991

Electrostatic orientation of the electron-transfer complex between plastocyanin and cytochrome c.

To understand the specificity and efficiency of protein-protein interactions promoting electron transfer, we evaluated the role of electrostatic forces in precollision orientation by the development of two new methods, computer graphics alignment of protein electrostatic fields and a systematic orientational search of intermolecular electrostatic energies for two proteins at present separation distances. We applied these methods to the plastocyanin/cytochrome c interaction, which is faster than random collision, but too slow for study by molecular dynamics techniques. Significant electrostatic potentials were concentrated on one-fourth (969 A2) of the plastocyanin surface, with the greatest negative potential centered on the Tyr-83 hydroxyl within the acidic patch, and on one-eighth (632 A2) of the cytochrome c surface, with the greatest positive potential centered near the exposed heme edge. Coherent electrostatic fields occurred only over these regions, suggesting that local, rather than global, charge complementarity controls productive recognition. The three energetically favored families of pre-collision orientations all directed the positive region surrounding the heme edge of cytochrome c toward the acidic patch of plastocyanin but differed in heme plane orientation. Analysis of electrostatic fields, electrostatic energies of precollision orientations with 12 and 6 A separation distances, and surface topographies suggested that the favored orientations should converge to productive complexes promoting a single electron-transfer pathway from the cytochrome c heme edge to Tyr-83 of plastocyanin. Direct interactions of the exposed Cu ligand in plastocyanin with the cytochrome c heme edge are not unfavorable sterically or electrostatically but should occur no faster than randomly, indicating that this is not the primary pathway for electron transfer.

Amino Acid Sequence↗
PubMed1991

Structure, function and properties of antibody binding sites.

Do antibody combining sites possess general properties that enable them to bind different antigens with varying affinities and to bind novel antigens? Here, we address this question by examining the physical and chemical characteristics most favourable for residues involved in antigen accommodation and binding. Amphipathic amino acids could readily tolerate the change of environment from hydrophilic to hydrophobic that occurs upon antibody-antigen complex formation. Residues that are large and can participate in a wide variety of van der Waals' and electrostatic interactions would permit binding to a range of antigens. Amino acids with flexible side-chains could generate a structurally plastic region, i.e. a binding site possessing the ability to mould itself around the antigen to improve complementarity of the interacting surfaces. Hence, antibodies could bind to an array of novel antigens using a limited set of residues interspersed with more unique residues to which greater binding specificity can be attributed. An individual antibody molecule could thus be cross-reactive and have the capacity to bind structurally similar ligands. The accommodation of variations in antigenic structure by modest combining site flexibility could make an important contribution to immune defence by allowing antibody binding to distinct but closely related pathogens. Tyr and Trp most readily fulfil these catholic physicochemical requirements and thus would be expected to be common in combining sites on theoretical grounds. Experimental support for this comes from three sources, (1) the high frequency of participation by these amino acids in the antigen binding observed in six crystallographically determined antibody-antigen complexes, (2) their frequent occurrence in the putative binding regions of antibodies as determined from structural and sequence data and (3) the potential for movement of their side-chains in known antibody binding sites and model systems. The six bound antigens comprise two small different haptens, non-overlapping regions of the same large protein and a 19 amino acid residue peptide. Out of a total of 85 complementarity determining region positions, only 37 locations (plus 3 framework) are directly involved in antigen interaction. Of these, light chain residue 91 is utilized by all the complexes examined, whilst light chain 32, light chain 96 and heavy chain 33 are employed by five out of the six. The binding sites in known antibody-antigen complexes as well as the postulated combining sites in free Fab fragments show similar characteristics with regard to the types of amino acids present. The possible role of other amino acids is also assessed.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acids↗
PubMed1990

Automated docking of substrates to proteins by simulated annealing.

The Metropolis technique of conformation searching is combined with rapid energy evaluation using molecular affinity potentials to give an efficient procedure for docking substrates to macromolecules of known structure. The procedure works well on a number of crystallographic test systems, functionally reproducing the observed binding modes of several substrates.

Acetylglucosamine↗
PubMed1990

Serials standards work: the next frontier.

Serials, one of the more complicated areas of library technical endeavors, has lacked the benefit of standards for a long time. Even now, with standards beginning to be available, the majority of institutions are not working within standard serials formats. A survey to determine the use of serials standards in libraries was conducted in 1988 by the American Library Association, Resources and Technical Services Division, Serials Section, Committee to Study Serials Standards. In the spring of 1988 a survey was sent to a group encompassing the Association of Research Libraries members, CONSER participants, United States Newspaper Program participants, Microform Project libraries, and some vendors and librarians who attended the Committee meetings on a regular basis. The survey questionnaire assessed the current level of serials standards awareness of librarians and vendors. Topics included the type of serials systems used, standards relevant to serials control and union listing and whether or not they are implemented, types and levels of training staff received in the application of standards, benefits of the standards, and areas where standards are most needed.

Cataloging↗
PubMed1987

Conditioned media from the injured lower vertebrate CNS promote neurite outgrowth from mammalian brain neurons in vitro.

Unlike most pathways of the mature mammalian central nervous system (CNS), the CNS of lower vertebrates can regenerate after jury, a capacity that may be due to the secretion of neurite-promoting factors from the injured CNS. We report that conditioned media (CM) from the injured optic nerve of the mature goldfish promoted marked neurite outgrowth from dissociated embryonic rat cortical and hindbrain neurons in serum-free, neuron-enriched culture. This property was not shared by CM from intact goldfish optic nerve, or from intact or injured optic nerve of mature rats. Neurite-promoting activity was obtained at concentrations as low as 100 ng total protein/ml of CM from injured goldfish optic nerve, and was associated with a distinctive morphology of neurite outgrowth. Due its properties of non-dialyzability, heat lability, and trypsin sensitivity, the neurite-promoting factor(s) appeared to be one or more protein species of MW greater than 12,000. Factors secreted by the regenerating CNS of lower vertebrates can directly promote outgrowth of mammalian CNS neurons.

Animals↗
PubMed1987

Probes for double helical DNA sequence information: molecular mechanics study of a proposed model.

The biological activity of many molecules which bind to double helical DNA is related to the sequence specificity of their binding. The development of new substances of this type is challenging; a general solution to the problem does not exist. A new mechanism for small molecule-duplex DNA interaction termed intercalative displacement is proposed. The approach is promising for the design of new substances which will recognize sequence information on DNA. Molecular mechanics calculations in the absence of solvent and counterions predict that the proposed model is structurally and energetically closely related to the well known process of standard intercalation. The implications of these calculations for experimental studies are discussed.

Base Composition↗
PubMed1986

Recognition and interactions controlling the assemblies of beta barrel domains.

We present a qualitative computer graphics approach to the characterization of forces important to the assembly of beta domains that should have general utility for examining protein interactions and assembly. In our approach, the nature of the molecular surface buried by the domain contacts, the specificity of the residue-to-residue interactions, and the identity of electrostatic, hydrophobic, and hydrophilic interactions are elucidated. These techniques are applied to the beta barrel domains of Cu, Zn superoxide dismutase (SOD), immunoglobulin Fab, and tomato bushy stunt virus coat protein (TBSV), a plant viral capsid protein. By looking at a set of proteins having different numbers of interacting beta domains, we have been able to see some of the variety and also some of the patterns common to these assembled domains. Strong beta domain interactions (identified by their biochemical integrity) are apparently due to chemical, electrostatic, and shape complementarity of the molecular surfaces buried from interaction with solvent molecules. Although the amount of hydrophobic buried surface area appears to correlate with the strength of the interaction, electrostatic forces appear to be important in both stabilizing and destabilizing specific contacts. In TBSV, analysis of electrostatic interactions may help explain mechanisms of subunit accommodation to different environments, particle expansion, and pathways of assembly. The possible molecular basis for observed differences in the stability and flexibility of the domain complexes is discussed.

Capsid↗
PubMed1983

Structure of tomato busy stunt virus IV. The virus particle at 2.9 A resolution.

The structure of tomato bushy stunt virus has been determined crystallographically to 2.9 A resolution. Details are presented of both the molecular structure and the methods by which it has been solved. The icosahedrally symmetric viral shell is composed of 180 protein subunits (Mr 43,000), with three similar but distinct modes of subunit bonding. This capacity for alternative packing is due to localized flexibility in the folded polypeptide (hinges between domains) and to multiple conformations for surface side-chains. The polypeptide backbone has an essentially invariant fold within a compact domain. A mechanism for correct positioning of the different modes of subunit interaction is evident from the structure of the TBSV particle. Thirty-five residues of the polypeptide chain fold in an ordered way on 60 of the 180 subunits, forming an internal framework. Interaction of folded domains with this framework permits accuracy of long-range geometry (correct curvature and closure) to be determined by unambiguous switching between alternative local contact angles. RNA packs tightly into the particle interior. Protein-RNA interactions occur through parts of the subunit that are flexibly linked to the well-ordered domains of the shell. This variable interaction imposes minimum restrictions on the folding of the RNA chain.

Amino Acid Sequence↗
PubMedDate not supplied

Automated docking of flexible ligands: applications of AutoDock.

AutoDock is a suite of C programs used to predict the bound conformations of a small, flexible ligand to a macromolecular target of known structure. The technique combines simulated annealing for conformation searching with a rapid grid-based method of energy evaluation. This paper reviews recent applications of the technique and describes the enhancements included in the current release.

Carrier Proteins↗
PubMedDate not supplied

Ionization state and molecular docking studies for the macrophage migration inhibitory factor: the role of lysine 32 in the catalytic mechanism.

The macrophage migration inhibitory factor (MIF) is a cytokine that is structurally similar to certain isomerases and for which multiple immune and catalytic roles have been proposed. Different catalytic activities have been reported for MIF, yet the exact mechanism by which MIF acts is not completely known. As a tautomerase, the enzyme uses a general acid-base mechanism of proton transfer in which the amino-terminal proline has been shown to function as the catalytic base. We report the results of molecular docking simulations of macrophage migration inhibitory factor with three substrates, D-dopachrome, L-dopachrome methyl ester and p-(hydroxyphenyl)pyruvate. Electrostatic pK(a) predictions were also performed for the free and complexed forms of the enzyme. The predicted binding mode of p-(hydroxyphenyl)pyruvate is in agreement with the recently published X-ray structure. A model for the binding mode of D-dopachrome and L-dopachrome methyl ester to MIF is proposed which offers insights into the catalytic mechanism of D-dopachrome tautomerase activity of MIF. The proposed catalytic mechanism is further supported by the pK(a) predictions, which suggest that residue Lys32 acts as the general acid for the enzymatic catalysis of D-dopachrome.

Catalysis↗
PubMedDate not supplied

The reactivity of anti-peptide antibodies is a function of the atomic mobility of sites in a protein.

To study the nature of antigenic recognition, antibodies have been prepared against a set of peptide sequences representing both highly mobile and well-ordered regions of myohaemerythrin, based on X-ray crystallographic temperature factors. Anti-peptide antibodies against highly mobile regions react strongly with the native protein; anti-peptide antibodies from well-ordered regions do not. Mobility is a major factor in the recognition of the native protein by anti-peptide antibodies; this may be of general significance in protein-protein interactions.

Animals↗