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  • Biochemistry and Biotechnology  (18)
  • Computational Chemistry and Molecular Modeling  (6)
  • molecular dynamics  (4)
  • HIV-1 aspartic proteinase  (1)
  • Helical peptide  (1)
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Material
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  • 1
    Electronic Resource
    Electronic Resource
    Design of dimerization inhibitors of HIV-1 aspartic proteinase: A computer-based combinatorial approach (2000)
    Springer
    Journal of computer aided molecular design 14 (2000), S. 161-179 
    Details
    ISSN: 1573-4951
    Keywords: de novo design ; finite-difference Poisson–Boltzmann ; HIV-1 aspartic proteinase ; inhibitors of dimerization ; MCSS ; structure-based drug design
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Inhibition of dimerization to the active form of the HIV-1 aspartic proteinase (HIV-1 PR) may be a way to decrease the probability of escape mutations for this viral protein. The Multiple Copy Simultaneous Search (MCSS) methodology was used to generate functionality maps for the dimerization interface of HIV-1 PR. The positions of the MCSS minima of 19 organic fragments, once postprocessed to take into account solvation effects, are in good agreement with experimental data on peptides that bind to the interface. The MCSS minima combined with an approach for computational combinatorial ligand design yielded a set of modified HIV-1 PR C-terminal peptides that are similar to known nanomolar inhibitors of HIV-1 PR dimerization. A number of N-substituted 2,5-diketopiperazines are predicted to be potential dimerization inhibitors of HIV-1 PR.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008146201260
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  • 2
    Electronic Resource
    Electronic Resource
    Adaptive umbrella sampling of the potential energy: modified updating procedure of the umbrella potential and application to peptide folding (1999)
    Springer
    Theoretical chemistry accounts 101 (1999), S. 62-66 
    Details
    ISSN: 1432-2234
    Keywords: Key words: Adaptive umbrella sampling ; Multicanonical sampling ; Helical peptide ; β-hairpin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract. Adaptive umbrella sampling of the potential energy is used as a search method to determine the structures and thermodynamics of peptides in solution. It leads to uniform sampling of the potential energy, so as to combine sampling of low-energy conformations that dominate the properties of the system at room temperature with sampling of high-energy conformations that are important for transitions between different minima. A modification of the procedure for updating the umbrella potential is introduced to increase the number of transitions between folded and unfolded conformations. The method does not depend on assumptions about the geometry of the native state. Two peptides with 12 and 13 residues, respectively, are studied using the CHARMM polar-hydrogen energy function and the analytical continuum solvent potential for treatment of solvation. In the original adaptive umbrella sampling simulations of the two peptides, two and six transitions occur between folded and unfolded conformations, respectively, over a simulation time of 10 ns. The modification increases the number of transitions to 6 and 12, respectively, in the same simulation time. The precision of estimates of the average effective energy of the system as a function of temperature and of the contributions to the average effective energy of folded conformations obtained with the adaptive methods is discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002140050407
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Estimation of uncertainties in X-ray refinement results by use of perturbed structures (1987)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 2 (1987), S. 1-12 
    Details
    ISSN: 0887-3585
    Keywords: protein crystallography ; protein refinement ; empirical energy simulations ; error analysis ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The uncertainties in the refined parameters for a 1.5-Å X-ray structure of carbon-monoxy (FeII) myoglobin are estimated by combining energy minimization with least-squares refinement against the X-ray data. The energy minimization, done without reference to the X-ray data, provide perturbed structures which are used to restart conventional X-ray refinement. The resulting refined structures have the same, or better, R-factor and stereochemical parameters as the original X-ray structure, but deviate from it by 0.13 Å rms for the backbone atoms and 0.31 Å rms for the sidechain atoms. Atoms interacting with a disordered sidechain, Arg 45 CD3, are observed to have larger positional uncertainties. The uncertainty in the B-factors, within the isotropic harmonic motion approximation, is estimated to be 15%. The resulting X-ray structures are more consistent with the energy parameters used in simulations.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340020102
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  • 4
    Electronic Resource
    Electronic Resource
    Exploration of disorder in protein structures by X-ray restrained molecular dynamics (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 340-358 
    Details
    ISSN: 0887-3585
    Keywords: ribonuclease A ; crambin ; conformational disorder ; protein crystallography ; simulated annealing ; X-ray refinement ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Conformational disorder in crystal structures of ribonuclease-A and crambin is studied by including two independent structures in least-squares optimizations against X-ray data. The optimizations are carried out by X-ray restrained molecular dynamics (simulated annealing refinement) and by conventional least-squares optimization. Starting from two identical structures, the optimizations against X-ray data lead to significant deviations between the two, with rms backbone displacements of 0.45 Å for refinement of ribonuclease at 1.53 Å resolution, and 0.31 Å for crambin at 0.945 Å. More than 15 independent X-ray restrained molecular dynamics runs have been carried out for ribonuclease, and the displacements between the resulting structures are highly reproducible for most atoms. These include residues with two or more conformations with significant dihedral angle differences and alternative hydrogen bonding, as well as groups of residues that undergo displacements that are suggestive of rigid-body librations. The crystallographic R-values obtained are ≈ 13%, as compared to 15.3% for a comparable refinement with a single structure. Least-squares optimization without an intervening restrained molecular dynamics stage is sufficient to reproduce most of the observed displacements. Similar results are obtained for crambin, where the higher resolution of the X-ray data allows for refinement of unconstrained individual anisotropic temperature factors. These are shown to be correlated with the displacements in the two-structure refinements.
    Additional Material: 10 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340100407
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  • 5
    Electronic Resource
    Electronic Resource
    Collective motions in proteins: A covariance analysis of atomic fluctuations in molecular dynamics and normal mode simulations (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 205-217 
    Details
    ISSN: 0887-3585
    Keywords: molecular dynamics ; normal modes ; collective motions ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A method is described for identifying collective motions in proteins from molecular dynamics trajectories or normal mode simulations. The method makes use of the covariances of atomic positional fluctuations. It is illustrated by an analysis of the bovine pancreatic trypsin inhibitor. Comparison of the covariance and cross-correlation matrices shows that the relative motions have many similar features in the different simulations. Many regions of the protein, especially regions of secondary structure, move in a correlated manner. Anharmonic effects, which are included in the molecular dynamics simulations but not in the normal analysis, are of some importance in determining the larger scale collective motions, but not the more local fluctuations. Comparisons of molecular dynamics simulations in the present and absence of solvent indicate that the environment is of significance for the long-range motions.
    Additional Material: 7 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110305
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  • 6
    Electronic Resource
    Electronic Resource
    A molecular dynamics analysis of protein structural elements (1989)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 5 (1989), S. 337-354 
    Details
    ISSN: 0887-3585
    Keywords: computer simulation ; fluctuations in proteins ; secondary structural dynamics ; lysozyme ; protein-substrate complex ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The relation between protein secondary structure and internal motions was examined by using molecular dynamics to calculate positional fluctuations of individual helix, β-sheet, and loop structural elements in free and substrate-bound hen egg-white lysozyme. The time development of the fluctuations revealed a general correspondence between structure and dynamics; the fluctuations of the helices and β-sheets converged within the 101 psec period of the simulation and were lower than average in magnitude, while the fluctuations of theloop regions were not converged and were mostly larger than average in magnitude. Notable exceptions to this pattern occurred in the substrate-bound simulation. A loop region (residues 101-107) of the active site cleft had significantly reduced motion due to interactions withthe substrate. Moreover, part of a loop and a 310 helix (residues of 67-88) not in contact with the substrate showeda marked increase in fluctuations. That these differences in dynamics of free and substrate-bound lysozyme did not result simply from sampling errors was established by an analysis of the variations in the fluctuationsof the two halves of the 101 psec simulation of free lysozyme. Concerted transitions of four to five mainchain φ and ψ angles between dihedral wells were shown to be responsible for large coordinate shifts in the loops. These transitions displaced six or fewer residues and took place eitherabruptly, in 1 psec or less, or with a diffusive character over 5-10 psec. Displacements of rigid secondary structures involved longer timescale motions in bound lysozyme; a 0.5 Å rms change in the position of a helix occurred over the 55 psec simulation period. This helix reorientation within the protein appears to be a response to substrate binding. There was little correlation between the solvent accessible surface areaand the dynamics of the different structural elements.
    Additional Material: 15 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340050409
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  • 7
    Electronic Resource
    Electronic Resource
    An automated method for dynamic ligand design (1995)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 23 (1995), S. 472-490 
    Details
    ISSN: 0887-3585
    Keywords: drug design ; FKBP ; FK506 ; immunophilin ; MCSS ; DLD ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: An automated method for the dynamic ligand design (DLD) for a binding site of known structure is described. The method can be used for the creation of de novo ligands and for the modification of existing ligands. The binding site is saturated with atoms (sp3 carbon atoms in the present implementation) that form molecules under the influence of a potential function that joins atoms to each other with the correct stereochemistry. The resulting molecules are linked to precomputed functional group minimum energy positions in the binding site. The generalized potential function allows atoms to sample a continuous parameter space that includes the Cartesian coordinates and their occupancy and type, e.g., the method allows change of an sp3 carbon into an sp2 carbon or oxygen. A parameter space formulated in this way can then be sampled and optimized by a variety of methods. In this work, molecules are generated by use of a Monte Carlo simulated annealing algorithm. The DLD method is illustrated by its application to the binding site of FK506 binding protein (FKBP), an immunophilin. De novo ligands are designed and modification of the immunosuppressant drug FK506 are suggested. The results demonstrate that the dynamic ligand design approach can automatically construct ligands which complement both the shape and charge distribution of the binding site. © 1995 Wiley-Liss, Inc.
    Additional Material: 9 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340230403
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  • 8
    Electronic Resource
    Electronic Resource
    Anisotropy and anharmonicity of atomic fluctuations in proteins: Analysis of a molecular dynamics simulation (1987)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 2 (1987), S. 236-259 
    Details
    ISSN: 0887-3585
    Keywords: atomic probability distributions of proteins ; anisotropy and anharmonicity of motions in proteins ; multiple occupancy of atomic positions in proteins ; molecular dynamics simulation ; lysozyme ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Positional probability density functions (pdf) for the atomic fluctuations are determined from a molecular dynamics simulation for hen egg-white lysozyme. Most atoms are found to have motions that are highly anisotropic but only slightly anharmonic. The largest deviations from harmonic motion are in the direction of the largest rms fluctuations in the local principal axis frame. Backbone atoms tend to be more nearly harmonic than sidechain atoms. The atoms with the largest anharmonicities tend to have pdfs with multiple peaks, each of which is close to harmonic. Several model pdfs are evaluated on the basis of how well they fit probability densities from the dynamics simulations when parameterized in terms of the moments of the distribution. Gram-Charlier and Edgeworth perturbation expansions, which have been successful in describing the motions of small molecules in crystals, are shown to be inadequate for the distributions found in the dynamics of proteins. Multipeaked distribution functions are found to be more appropriate.
    Additional Material: 11 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340020308
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  • 9
    Electronic Resource
    Electronic Resource
    Polar hydrogen positions in proteins: Empirical energy placement and neutron diffraction comparison (1988)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 4 (1988), S. 148-156 
    Details
    ISSN: 0887-3585
    Keywords: Protein structure ; empirical energy ; energy minimization ; molecular dynamics ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A method for the prediction of hydrogen positions in proteins is presented. The method is based on the knowledge of the heavy atom positions obtained, for instance, from X-ray crystallography. It employs an energy minimization limited to the environment of the hydrogen atoms bound to a common heavy atom or to a single water molecule. The method is not restricted to proteins and can be applied without modification to nonpolar hydrogens and to nucleic acids. The method has been applied to the neutron diffraction structures of trypsin ribonuclease A, and bovine pancreatic trypsin inhibitor. A comparison of the constructed and the observed hydrogen positions shows few deviations except in situations in which several energetically similar conformations are possible. Analysis of the potential energy of rotation of Lys amino and Ser, Thr, Tyr hydroxyl groups reveals that the conformations of lowest intrinsic torsion energies are statistically favored in both the crystal and the constructed structures.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340040208
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  • 10
    Electronic Resource
    Electronic Resource
    The contribution of cross-links to protein stability: A normal mode analysis of the configurational entropy of the native state (1993)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 15 (1993), S. 71-79 
    Details
    ISSN: 0887-3585
    Keywords: disulfide bonds ; protein stability ; entropy of proteins ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The vibrational entropy of native BPTI, with three disulfide bonds, was determined by use of normal mode calculations and compared with that of folded variants having either one less disulfide bond or lacking a peptide bond at the trypsin-reactive site. Favorable contributions to the free energy of 2.5-5.1 kcal/mol at 300 K were calculated for the reduction of disulfide bonds in the folded state, whereas no favorable contribution was found for the hydrolysis of the peptide bond cleaved by trypsin. This is on the order of the effect of disulfides in the unfolded state. The implications of these results for the stabilization of a folded protein by the introduction of crosslinks are discussed. © 1993 Wiley-Liss, Inc.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340150109
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