Biomedical subjects

A J Olson

Publications and source records attributed to A J Olson.

At least 37 records · Page 2Linked to original sources

PubMed1998

Interactive modeling of supramolecular assemblies.

The modeling of supramolecular structure presents two major challenges: (1) managing the large amount of sequence, structural and biochemical data, and (2) presenting the data to the user in a flexible and comprehensible manner that addresses these problems. We describe a visualization environment for the creation and analysis of supramolecular models. A set of modular symmetry tools, collectively called SymGen, has been created, providing a flexible platform for the creation of complex assemblies, with interactive control of all symmetry elements and their parameters. A second tool, SymSearch, allows a range of parameters defined within SymGen to be sampled and the resulting conformations to be evaluated. The environment avoids information overload, caused by the large number of atoms in supramolecular complexes, by using a multiresolution spherical harmonic representation that allows the user to display only essential features. Spherical harmonics also enables control of the triangulation level, allowing the user to reduce the complexity of the geometric description to retain interactive speed. The visual fidelity of the surface data is retained by using texture maps that are independent of the resolution of the underlying triangulation. We describe the design and implementation of this environment, and three illustrative examples of its utility.

Capsid↗

PubMed1998

Visualizing the future of molecular graphics.

The field of computer graphics has played an important role in the advancement of structural molecular biology and in the development of structure-based drug design. This article will provide a brief background on the development of this technology, and then focus on the current trends and future directions in molecular graphics and how they will impact the practice of molecular modeling and design. Specific areas that will be covered include: 1) the development of surface and volume based representations of molecular properties and interactions; 2) new approaches to modeling flexible and multi-component structures, and 3) the impact of object-oriented graphics-based programming and the rapidly growing use of network based computing.

Computer Graphics↗

PubMed1998

Automated docking and the search for HIV protease inhibitors.

This article will discuss the motivations, technologies, and future directions of computational automated docking in the context of the structure-based rational design of HIV-1 protease inhibitors. Docking simulations are widely used for screening of compound libraries to identify new drug leads, employing a simple model for rapid testing of thousands of compounds. Docking simulations are also useful for lead enhancement, using more detailed models to analyze the atomic interactions between inhibitors and target macromolecules. Major advances have been reported in the development of empirical force fields, which now allow assessment of relative binding strength and drug specificity, and extensions of automated docking techniques allow de novo drug design.

Computer Simulation↗

PubMed1998

Computational coevolution of antiviral drug resistance.

An understanding of antiviral drug resistance is important in the design of effective drugs. Comprehensive features of the interaction between drug designs and resistance mutations are difficult to study experimentally because of the very large numbers of drugs and mutants involved. We describe a computational framework for studying antiviral drug resistance. Data on HIV-1 protease are used to derive an approximate model that predicts interaction of a wide range of mutant forms of the protease with a broad class of protease inhibitors. An algorithm based on competitive coevolution is used to find highly resistant mutant forms of the protease, and effective inhibitors against such mutants, in the context of the model. We use this method to characterize general features of inhibitors that are effective in overcoming resistance, and to study related issues of selection pathways, cross-resistance, and combination therapies.

Algorithms↗

PubMed1997

Configurational transitions in Fourier series-represented DNA supercoils.

A new Fourier series representation of supercoiled DNA is employed in Langevin dynamics simulations to study large-scale configurational motions of intermediate-length chains. The polymer is modeled as an ideal elastic rod subject to long-range van der Waals' interactions. The van der Waals' term prevents the self-contact of distant chain segments and also mimics attractive forces thought to stabilize the association of closely spaced charged rods. The finite Fourier series-derived polymer formulation is an alternative to the piecewise B-spline curves used in past work to describe the motion of smoothly deformed supercoiled DNA in terms of a limited number of independent variables. This study focuses on two large-scale configurational events: the interconversion between circular and figure-8 forms at a relatively low level of supercoiling, and the transformation between branched and interwound structures at a higher superhelical density.

Biophysical Phenomena↗

PubMed1997

Recognition of protein structure on coarse lattices with residue-residue energy functions.

We suggest and test potentials for the modeling of protein structure on coarse lattices. The coarser the lattice, the more complete and faster is the exploration of the conformational space of a molecule. However, there are inevitable energy errors in lattice modeling caused by distortions in distances between interacting residues; the coarser the lattice, the larger are the energy errors. It is generally believed that an improvement in the accuracy of lattice modelling can be achieved only by reducing the lattice spacing. We reduce the errors on coarse lattices with lattice-adapted potentials. Two methods are used: in the first approach, 'lattice-derived' potentials are obtained directly from a database of lattice models of protein structure; in the second approach, we derive 'lattice-adjusted' potentials using our previously developed method of statistical adjustment of the 'off-lattice' energy functions for lattices. The derivation of off-lattice Calpha atom-based distance-dependent pairwise potentials has been reported previously. The accuracy of 'lattice-derived', 'lattice-adjusted' and 'off-lattice' potentials is estimated in threading tests. It is shown that 'lattice-derived' and 'lattice-adjusted' potentials give virtually the same accuracy and ensure reasonable protein fold recognition on the coarsest considered lattice (spacing 3.8 A), however, the 'off-lattice' potentials, which efficiently recognize off-lattice folds, do not work on this lattice, mainly because of the errors in short-range interactions between neighboring residues.

Models, Chemical↗

PubMed1997

Residue-residue mean-force potentials for protein structure recognition.

We present two new sets of energy functions for protein structure recognition, given the primary sequence of amino acids along the polypeptide chain. The first set of potentials is based on the positions of alpha- and the second on positions of beta- and alpha-carbon atoms of amino acid residues. The potentials are derived using a theory of Boltzmann-like statistics of protein structure. The energy terms incorporate both long-range interactions between residues remote along a chain and short-range interactions between near neighbors. Distance dependence is approximated by a piecewise constant function defined on intervals of equal size. The size of the interval is optimized to preserve as much detail as possible without introducing excessive error due to limited statistics. A database of 214 non-homologous proteins was used both for the derivation of the potentials, and for the 'threading' test originally suggested by Hendlich et al. (1990) J. Mol. Biol., 216, 167-180. Special care is taken to avoid systematic error in this test. For threading, we used 100 non-homologous protein chains of 60-205 residues. The energy of each of the native structures was compared with the energy of 43,000 to 19,000 alternative structures generated by threading. Of these 100 native structures, 92 have the lowest energy with alpha-carbon-based potentials and, even more, 98 of these 100 structures, have the lowest energy with the beta- and alpha-carbon based potentials.

Databases, Factual↗

PubMed1997

Molecular analysis of the feline immunodeficiency virus protease: generation of a novel form of the protease by autoproteolysis and construction of cleavage-resistant proteases.

The feline immunodeficiency virus (FIV) protease is essential for virion maturation and subsequent viral replication in that it cleaves the Gag and Gag/Pol polyproteins at eight sites to release the respective structural proteins and enzymes. During purification of a recombinant FIV protease (PR), we noted that it underwent autoproteolysis (autolysis) to give discrete cleavage products. These additional PR cleavage sites were defined using N-terminal amino acid sequence analysis and mass spectrometry. Protease breakdown products were also found in FIV virions and were of the same apparent molecular weights as the in vitro autolysis products. Four primary PR autolysis sites were blocked via substitution of either the P1 amino acid with a beta-branched amino acid or the P1' amino acid with lysine. Cleavage-resistant PRs which had Km and k(cat) values similar to those of FIV PR were constructed. An autolysis time course determined that blocking all four primary autolysis sites yielded a cleavage-resistant PR which was enzymatically stable. Concomitant with autolysis is the generation of an N-terminally truncated form of the PR (Thr6/PR) which has enhanced stability with respect to that of FIV PR. A structural basis for the Thr6/PR activity is presented, as are the possible roles of autolysis in the viral replication cycle.

Animals↗

PubMed1997

Accurate mean-force pairwise-residue potentials for discrimination of protein folds.

We present two new sets of energy functions for protein structure recognition. The first set of potentials is based on the positions of alpha- and the second on positions of beta-carbon atoms of amino acid residues. The potentials are derived using a theory of Boltzmann-like statistics of protein structure by Finkelstein et al. The energy terms incorporate both long-range interactions between residues remote along a chain and short-range interactions between near neighbors. Distance-dependence is approximated by a piecewise constant function defined on intervals of equal size. The size of this interval is optimized. A database of 222 non-homologous proteins was used both for the derivation of the potentials, and for the "threading" test originally suggested by Hendlich et al. For threading, we used 102 non-homologous protein chains of 60 to 200 residues. The energy of each of the native structures was compared with the energy of 45 to 20 thousand alternative structures generated by threading. Of these 102 native structures 94 have the lowest energy with alpha-carbon-based potentials, and even more, 100 of these 102 structures, have the lowest energy with the beta-carbon-based potentials.

Computer Simulation↗

PubMed1997

Real time surface reconstruction for moving molecular fragments.

Recently we introduced the Reduced Surface as an efficient tool to built molecular surfaces. We describe here how this geometric construct can be used to efficiently reconstruct the solvent excluded surface of a protein for which the coordinates of a subset of atoms are changing. We show that, the complexity of that operation is not dependent upon the size of the molecule and is in O[tlog(t)] where t is the maximum of the number of probes and atoms involved in the reconstruction of the surface. The algorithms described here have been implemented and tested on several proteins. The triangulation of the solvent excluded surface of proteins in which a side chain was changing conformation could be updated at rates ranging from 7 to 22 frames per second. We also applied this method to compute the surface area fluctuation of the FIV protease undergoing a constrained molecular dynamics simulation (16 mobile residues). Rate of 6 frames per second were obtained in this case.

Algorithms↗

PubMed1996

Adjusting potential energy functions for lattice models of chain molecules.

Lattice models of proteins can approximate off-lattice structure to arbitrary precision with RMS (root mean squared) deviations roughly equal to half the lattice spacing (Rykunov et al., Proteins 22:100-109, 1995; Reva et al., J. Comp. Biol., 1996). However, even small distortions in the positions of chain links lead to significant errors in lattice-based energy calculations (Reva et al., J. Comp. Chem., 1996). These errors arise mainly from rigid interactions (such as steric repulsion) which change their energies considerably at a range which is much smaller than the usual accuracy of lattice modeling (> 1.0 A). To reduce this error, we suggest a procedure of adjusting energy functions to a given lattice. The general approach is illustrated with energy calculations based on pairwise potentials by Kolinski et al. (J. Chem. Phys. 98:1-14, 1993). At all the lattice spacings, from 0.5-3.8 A, the lattice-adjusted potentials improve the accuracy of lattice-based energy calculations and increase the correlations between off-lattice and lattice energies.

Models, Chemical↗

PubMed1996

Building self-avoiding lattice models of proteins using a self-consistent field optimization.

We present an algorithm to build self-avoiding lattice models of chain molecules with low RMS deviation from their actual 3D structures. To find the optimal coordinates for the lattice chain model, we minimize a function that consists of three terms: (1) the sum of squared deviations of link coordinates on a lattice from their off-lattice values, (2) the sum of "short-range" terms, penalizing violation of chain connectivity, and (3) the sum of "long-range" repulsive terms, penalizing chain self-intersections. We treat this function as a chain molecule "energy" and minimize it using self-consistent field (SCF) theory to represent the pairwise link repulsions as 3D fields acting on the links. The statistical mechanics of chain molecules enables computation of the chain distribution in this field on the lattice. The field is refined by iteration to become self-consistent with the chain distribution, then dynamic programming is used to find the optimal lattice model as the "lowest-energy" chain pathway in this SCF. We have tested the method on one of the coarsest (and most difficult) lattices used for model building on proteins of all structural types and show that the method is adequate for building self-avoiding models of proteins with low RMS deviations from the actual structures.

Algorithms↗

PubMed1996

Reduced surface: an efficient way to compute molecular surfaces.

Because of their wide use in molecular modeling, methods to compute molecular surfaces have received a lot of interest in recent years. However, most of the proposed algorithms compute the analytical representation of only the solvent-accessible surface. There are a few programs that compute the analytical representation of the solvent-excluded surface, but they often have problems handling singular cases of self-intersecting surfaces and tend to fail on large molecules (more than 10,000 atoms). We describe here a program called MSMS, which is shown to be fast and reliable in computing molecular surfaces. It relies on the use of the reduced surface that is briefly defined here and from which the solvent-accessible and solvent-excluded surfaces are computed. The four algorithms composing MSMS are described and their complexity is analyzed. Special attention is given to the handling of self-intersecting parts of the solvent-excluded surface called singularities. The program has been compared with Connolly's program PQMS [M.L. Connolly (1993) Journal of Molecular Graphics, Vol. 11, pp. 139-141] on a set of 709 molecules taken from the Brookhaven Data Base. MSMS was able to compute topologically correct surfaces for each molecule in the set. Moreover, the actual time spent to compute surfaces is in agreement with the theoretical complexity of the program, which is shown to be O[n log(n)] for n atoms. On a Hewlett-Packard 9000/735 workstation, MSMS takes 0.73 s to produce a triangulated solvent-excluded surface for crambin (1 crn, 46 residues, 327 atoms, 4772 triangles), 4.6 s for thermolysin (3tln, 316 residues, 2437 atoms, 26462 triangles), and 104.53 s for glutamine synthetase (2gls, 5676 residues, 43632 atoms, 476665 triangles).

Chemistry, Physical↗

PubMed1996

Distributed automated docking of flexible ligands to proteins: parallel applications of AutoDock 2.4.

AutoDock 2.4 predicts the bound conformations of a small, flexible ligand to a nonflexible macromolecular target of known structure. The technique combines simulated annealing for conformation searching with a rapid grid-based method of energy evaluation based on the AMBER force field. AutoDock has been optimized in performance without sacrificing accuracy; it incorporates many enhancements and additions, including an intuitive interface. We have developed a set of tools for launching and analyzing many independent docking jobs in parallel on a heterogeneous network of UNIX-based workstations. This paper describes the current release, and the results of a suite of diverse test systems. We also present the results of a systematic investigation into the effects of varying simulated-annealing parameters on molecular docking. We show that even for ligands with a large number of degrees of freedom, root-mean-square deviations of less than 1 A from the crystallographic conformation are obtained for the lowest-energy dockings, although fewer dockings find the crystallographic conformation when there are more degrees of freedom.

Azepines↗

PubMed1995

Texture mapping parametric molecular surfaces.

Texture mapping is an increasingly popular technique in molecular modeling. It is particularly effective in representing high-resolution surface detail using a low-resolution polygonal model. We describe how texture mapping can be used with parametric molecular surfaces represented as expansions of spherical harmonic functions. We define analytically the texture image and its transformation to a parametric surface. Unlike most methods of texture mapping, this transformation defines a one-to-one correspondence between the surface and the texture; texture coordinates are derived from the location of the surface point and not from physical properties at the surface point. This has advantages for the interactive visualization of surface data. We control the interactive response time by lowering the resolution of the polygon mesh while retaining the high-resolution detail of the texture, or we can lower the resolution of the texture image with the same polygonal model. By using a well-defined convention for texture coordinates, we can use the same image for the original surface or its parametric representation, and we can rapidly switch between images that represent different surface properties without recomputing the texture coordinates. Parametric surfaces allow new flexibility for the visualization of molecular surface data.

Aprotinin↗

PubMed1995

Approximation and visualization of large-scale motion of protein surfaces.

We present a method for the approximation and real-time visualization of large-scale motion of protein surfaces. A molecular surface is represented by an expansion of spherical harmonic functions, and the motion of protein atoms around their equilibrium positions is computed by normal mode analysis. The motion of the surface is approximated by projecting the normal mode vectors of the solvent-accessible atoms to the spherical harmonic representation of the molecular surface. These surface motion vectors are represented by a separate spherical harmonic expansion. Representing the surface geometry and the surface motion vectors by spherical harmonic expansions allows variable-resolution analysis and real-time display of the large-scale surface motion. This technique has been applied to interactive visualization, interactive surface manipulation, and animation.

Computer Graphics↗

PubMed1995

Biomolecular visualization using AVS.

Dataflow systems for scientific visualization are becoming increasingly sophisticated in their architecture and functionality. AVS, from Advanced Visual Systems Inc., is a powerful dataflow environment that has been applied to many computation and visualization tasks. An important, yet complex, application area is molecular modeling and biomolecular visualization. Problems in biomolecular visualization tax the capability of dataflow systems because of the diversity of operations that are required and because many operations do not fit neatly into the dataflow paradigm. Here we describe visualization strategies and auxiliary programs developed to enhance the applicability of AVS for molecular modelling. Our visualization strategy is to use general-purpose AVS modules and a small number of chemistry-specific modules. We have developed methods to control AVS using AVS-tool, a programmable interface to the AVS Command Line Interpreter (CLI), and have also developed NAB, a C-like language for writing AVS modules that has extensions for operating on proteins and nucleic acids. This strategy provides a flexible and extensible framework for a wide variety of molecular modeling tasks.

Artificial Intelligence↗

PubMed1995

Constructing lattice models of protein chains with side groups.

An algorithm to construct lattice models of polymers with side chains is presented. A search for the global minimum of the error function for a given lattice-to-chain orientation is done by dynamic programming, making the search both fast and complete. Application of the algorithm is illustrated by constructing lattice models for 12 proteins of different sizes and structural types.

Algorithms↗