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  • 1
    Keywords: PEPTIDE ; SIMULATIONS ; SPECTRA ; Germany ; PROTEINS ; DYNAMICS ; SIMULATION ; PARAMETERS ; VACCINE ; KINETICS ; ALPHA-HELIX ; CD4-BINDING DOMAIN ; CONFORMATIONAL SWITCH ; EXPLICIT SOLVENT WATER ; GP120 ; IMMUNOGENIC PEPTIDE ; molecular dynamics simulation,peptide,convergence ; MOLECULAR-DYNAMICS SIMULATION ; TRIFLUOROETHANOL
    Abstract: To examine the conformational properties in aqueous solution of a 15-residue peptide that is a potential pharmacophore for AIDS vaccine development, molecular dynamics simulations were performed in water starting from structures determined experimentally in three different organic solvents. Convergence characteristics of the simulation are examined in Cartesian and conformational spaces. In addition, novel analysis tools are employed including a multidimensional scaling method to represent the distance between trajectory frames. As these methods are based on a variety of physical parameters, they provide a useful cross-check on the structural convergence. Theoretical two-dimensional (2D) H-1-NMR spectra are also generated. These are superficially quite different in appearance, demonstrating that backbone similarities difficult to identify by visual inspection of 2D NMR data can be revealed using the methods described here. (C) 2003 Wiley Periodicals, Inc
    Type of Publication: Journal article published
    PubMed ID: 14517902
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  • 2
    Keywords: ENERGIES ; CELL ; Germany ; PATHWAY ; PATHWAYS ; PROTEIN ; RELEASE ; MECHANISM ; primary ; PROTON ; WATER ; TRANSPORT ; ENERGY ; MEMBRANE ; RATES ; STRATEGIES ; TRANSLOCATION ; ANGSTROM RESOLUTION ; MOLECULAR-MECHANISM ; BACTERIORHODOPSIN PHOTOCYCLE ; CRYSTALLOGRAPHIC STRUCTURE ; PHOTOCYCLE ; PROTON-TRANSFER ; SCHIFF-BASE ; SOLID-STATE NMR
    Abstract: Recent structures of putative intermediates in the bacteriorhodopsin photocycle have provided valuable snapshots of the mechanism by which protons are pumped across the membrane. However, key steps remain highly controversial, particularly the proton transfer occurring immediately after retinal trans--〉cis photoisomerization. The gradual release of stored energy is inherently nonequilibrium: which photocycle intermediates are populated depends not only on their energy but also on their interconversion rates. To understand why the photocycle follows a productive (i.e., pumping), rather than some unproductive, relaxation pathway, it is necessary to know the relative energy barriers of individual steps. To discriminate between the many proposed scenarios of this process, we computed all its possible minimum-energy paths. This reveals that not one, but three very different pathways have energy barriers consistent with experiment. This result reconciles the conflicting views held on the mechanism and suggests a strategy by which the protein renders this essential step resilient
    Type of Publication: Journal article published
    PubMed ID: 15242604
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  • 3
    Keywords: PEPTIDE ; Germany ; COMMON ; PROTEIN ; PROTEINS ; DOMAIN ; ANTIGEN ; DYNAMICS ; SIMULATION ; SEQUENCE ; SEQUENCES ; antibodies ; antibody ; TARGET ; DESIGN ; VARIABILITY ; VACCINE ; STRATEGIES ; PREDICTION ; GP120 ; MOLECULAR-DYNAMICS ; HIV-1 ; GENOMIC DIVERSITY ; HTLV-III ; MINIMIZATION
    Abstract: The most promising target antigen for an HIV vaccine designed using the classic antibody strategy has been the viral coat protein gp120. Unfortunately, its high variability has prevented this approach. We examine here a 15-residue peptide derived from the CD4-binding domain of gp120. By use of molecular dynamics computer simulation, it is shown that despite considerable sequence variation, the three-dimensional structure of the peptide is preserved over the full range of clade-specific sequences. Furthermore, sequences threaded onto the structure exhibit common three-dimensional electrostatic and hydrophobic properties. These common physicochemical characteristics constitute a pharmacophoric footprint that promises to be useful in the design of a synthetic antigen for vaccine development
    Type of Publication: Journal article published
    PubMed ID: 15239651
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  • 4
    Keywords: PEPTIDE ; SECONDARY STRUCTURE ; MOLECULAR-DYNAMICS SIMULATIONS ; SALT ; H4 ; CORE PARTICLE ; H4-K16 ACETYLATION ; MESOSCOPIC OLIGONUCLEOSOME MODEL ; MONTE-CARLO METHOD ; FORCE-FIELDS
    Abstract: Histone tails play an important role in gene transcription and expression. We present here a systematic computational study of the role of histone tails in the nucleosome, using replica exchange molecular dynamics simulations with an implicit solvent model and different well-established force fields. We performed simulations for all four histone tails, H4, H3, H2A, and H2B, isolated and with inclusion of the nucleosome. The results confirm predictions of previous theoretical studies for the secondary structure of the isolated tails but show a strong dependence on the force field used. In the presence of the entire nucleosome for all force fields, the secondary structure of the histone tails is destabilized. Specific contacts are found between charged lysine and arginine residues and DNA phosphate groups and other binding sites in the minor and major DNA grooves. Using cluster analysis, we found a single dominant configuration of binding to DNA for the H4 and H2A histone tails, whereas H3 and H2B show multiple binding configurations with an equal probability. The leading stabilizing contribution for those binding configurations is the attractive interaction between the positively charged lysine and arginine residues and the negatively charged phosphate groups, and thus the resulting charge neutralization. Finally, we present results of molecular dynamics simulations in explicit solvent to confirm our conclusions. Results from both implicit and explicit solvent models show that large portions of the histone tails are not bound to DNA, supporting the complex role of these tails in gene transcription and expression and making them possible candidates for binding sites of transcription factors, enzymes, and other proteins.
    Type of Publication: Journal article published
    PubMed ID: 25517156
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  • 5
    Keywords: ENERGIES ; Germany ; PATHWAY ; PATHWAYS ; PROTEIN ; COMPLEX ; COMPLEXES ; PROTON ; SPECTROSCOPY ; WATER ; TRANSPORT ; ENERGY ; MOTION ; BACTERIORHODOPSIN PHOTOCYCLE ; bacteriorhodopsin,quantum mechanical/molecular mechanical,adiabatic mapping,conjugate peak refinemen
    Abstract: We have combined the Quantum Mechanical/Molecular Mechanical (QM/MM) computational approach with techniques that search for minimum energy reaction paths to investigate retinal deprotonation in the light-driven proton pump protein, bacteriorhodopsin. The calculations indicate that the commonly used adiabatic mapping method can lead to misleading energy barriers when too simple reaction coordinates are selected. The use of a reaction search method that does not require the a priori definition of a reaction coordinate allows to find multiple low-energy retinal deprotonation pathways whose energy barriers are fully characterized
    Type of Publication: Journal article published
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  • 6
    Keywords: ENERGIES ; ENVIRONMENT ; Germany ; PATHWAY ; PATHWAYS ; PROTEIN ; BASE ; PROTON ; WATER ; TRANSPORT ; ENERGY ; REGION ; PRODUCT ; STRUCTURAL-CHANGES ; REVEALS ; ORIENTATION ; AFFINITY ; BOND ; MOLECULAR-DYNAMICS ; PROTON-TRANSFER ; SCHIFF-BASE ; SOLID-STATE NMR ; CHARGE-DENSITY ; DARK-ADAPTED BACTERIORHODOPSIN ; DETERMINANTS ; ELECTRONIC POLARIZATION ; HALOBACTERIUM-HALOBIUM ; PROTEIN ENVIRONMENT ; RETINAL SCHIFF-BASE ; WATER-MOLECULES
    Abstract: The first proton transport step following photon absorption in bacteriorhodopsin is from the 13-cis retinal Schiff base to Asp85. Configurational and energetic determinants of this step are investigated here by performing quantum mechanical/molecular mechanical minimum-energy reaction-path calculations. The results suggest that retinal can pump protons when in the 13-cis, 15-anti conformation but not when 13-cis, 15-syn. Decomposition of the proton transfer energy profiles for various possible pathways reveals a conflict between the effect of the intrinsic proton affinities of the Schiff base and Asp85, which favors the neutral, product state (i.e., with Asp85 protonated), with the mainly electrostatic interaction between the protein environment with the reacting partners, which favors the ion pair reactant state (i.e., with retinal protonated). The rate-limiting proton-transfer barrier depends both on the relative orientations of the proton donor and acceptor groups and on the pathway followed by the proton; depending on these factors, the barrier may arise from breaking and forming of hydrogen bonds involving the Schiff base, Asp85, Asp212, and water w402, and from nonbonded interactions involving protein groups that respond to the charge rearrangements in the Schiff base region
    Type of Publication: Journal article published
    PubMed ID: 15521787
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  • 7
    Keywords: ENERGIES ; Germany ; SITE ; PROTEIN ; RESOLUTION ; DYNAMICS ; PROTON ; ENERGY ; STRUCTURAL-CHANGES ; PROTON-TRANSFER ; SCHIFF-BASE ; INTERMEDIATE ; EVENTS ; bacteriorhodopsin ; proton transfer ; ENERGY-STORAGE ; PHOTOISOMERIZATION
    Abstract: Productive proton pumping by bacteriorhodopsin requires that, after the all-trans to 13-cis photoisomerization of the retinal chromophore, the photocycle proceeds with proton transfer and not with thermal back-isomerization. The question of how the protein controls these events in the active site is addressed here using quantum mechanical/molecular mechanical reaction-path calculations. The results indicate that, while retinal twisting, significantly contributes to lowering the barrier for the thermal cis-trans back-isomerization, the rate-limiting barrier for this isomerization is still 5-6 kcal/mol larger than that for the first proton-transfer step. In this way, the retinal twisting is finely tuned so as to store energy to drive the subsequent photocycle while preventing wasteful back-isomerization
    Type of Publication: Journal article published
    PubMed ID: 16852870
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  • 8
    Keywords: CELL ; Germany ; SITE ; PROTEIN ; MOLECULES ; MECHANISM ; IMPACT ; BIOLOGY ; SUPPRESSION ; MOLECULE ; WATER ; ELEMENTS ; NUMBER ; ANGSTROM RESOLUTION ; MOLECULAR-DYNAMICS SIMULATIONS ; CONFORMATIONAL-CHANGES ; CRYSTALLOGRAPHIC STRUCTURE ; HALOBACTERIUM-HALOBIUM ; WATER-MOLECULES ; REARRANGEMENT ; analysis ; QM/MM ; SET ; retinal ; bacteriorhodopsin proton-transfer mechanism ; ION TRANSLOCATION ; M-INTERMEDIATE ; N-INTERMEDIATE ; reaction pathways ; RESONANCE RAMAN
    Abstract: The transfer of a proton from the retinal Schiff base to the nearby Asp85 protein group is an essential step in the directional proton-pumping by bacteriorhodopsin. To avoid the wasteful back reprotonation of the Schiff base from Asp85, the protein must ensure that, following Schiff base deprotonation, the energy barrier for back proton-transfer from Asp85 to the Schiff base is larger than that for proton-transfer from the Schiff base to Asp85. Here, three structural elements that may contribute to suppressing the back proton-transfer from Asp85 to the Schiff base are investigated: (i) retinal twisting; (ii) hydrogen-bonding distances in the active site; and (iii) the number and location of internal water molecules. The impact of the pattern of bond twisting on the retinal deprotonation energy is dissected by performing an extensive set of quantum-mechanical calculations. Structural rearrangements in the active site, such as changes of the Thr89:Asp85 distance and relocation of water molecules hydrogen-bonding to the Asp85 acceptor group, may participate in the mechanism which ensures that following the transfer of the Schiff base proton to Asp85 the protein proceeds with the subsequent photocycle steps, and not with back proton transfer from Asp85 to the Schiff base. (c) 2006 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17189704
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  • 9
    Keywords: ENERGIES ; SITE ; SITES ; PROTEIN ; MOLECULES ; TIME ; MECHANISM ; BASE ; DYNAMICS ; SIMULATION ; MOLECULE ; PROTON ; WATER ; STAGE ; ENERGY ; STRUCTURAL-CHANGES ; MOLECULAR-DYNAMICS ; molecular ; CHEMISTRY ; CRYSTALLOGRAPHIC STRUCTURE ; RETINAL SCHIFF-BASE ; interaction ; proton transfer ; USA ; NOV ; INSERTION ; molecular dynamics ; interactions ; CYTOCHROME-C-OXIDASE ; dynamic ; DYNAMICS SIMULATIONS ; FREE-ENERGY CALCULATIONS ; HISTOGRAM ANALYSIS METHOD ; L-INTERMEDIATE ; PROBABILITY ; STATE ; TIGHT-BINDING ; TRANSITION-STATE ANALOG
    Abstract: The functional mechanism of the light-driven proton pump protein bacteriorhodopsin depends on the location of water molecules in the active site at various stages of the photocycle and on their roles in the protontransfer steps. Here, free energy computations indicate that electrostatic interactions favor the presence of a cytoplasmic-side water molecule hydrogen bonding to the retinal Schiff base in the state preceding proton transfer from the retinal Schiff base to Asp85. However, the nonequilibrium nature of the pumping process means that the probability of occupancy of a water molecule in a given site depends both on the free energies of insertion of the water molecule in this and other sites during the preceding photocycle steps and on the kinetic accessibility of these sites on the time scale of the reaction steps. The presence of the cytoplasmicside water molecule has a dramatic effect on the mechanism of proton transfer: the proton is channeled on the Thr89 side of the retinal, whereas the transfer on the Asp212 side is hindered. Reaction-path simulations and molecular dynamics simulations indicate that the presence of the cytoplasmic-side water molecule permits a low-energy bacteriorhodopsin conformer in which the water molecule bridges the twisted retinal Schiff base and the proton acceptor Asp85. From this low-energy conformer, proton transfer occurs via a concerted mechanism in which the water molecule participates as an intermediate proton carrier
    Type of Publication: Journal article published
    PubMed ID: 18973373
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  • 10
    Keywords: RECEPTOR ; CELL ; Germany ; MODEL ; DENSITY ; VOLUME ; GENE ; TRANSDUCTION ; ACTIVATION ; COMPLEX ; RESPONSES ; COMPLEXES ; DOMAIN ; BIOLOGY ; MOLECULAR-BIOLOGY ; signal transduction ; SIGNAL ; MUTANT ; AMPLIFICATION ; SIGNAL-TRANSDUCTION ; EFFICIENT ; LOCALIZATION ; PROGENITOR CELLS ; CELL-SURFACE ; point mutation ; DIMERIZATION ; DOMAINS ; ERYTHROPOIETIN ; ERYTHROPOIETIN RECEPTOR ; LAYER ; OLIGOMERIZATION ; signaling ; molecular biology ; molecular ; RE ; VARIANT ; RESPONSIVENESS ; analysis ; MUTANTS ; TRANSMEMBRANE DOMAIN ; USA ; correlation ; SET ; NOV ; correlates ; modeling ; response ; erythrocytosis ; FUNCTIONALITY ; biological ; MEMBRANE-PROTEINS ; PRIMARY FAMILIAL POLYCYTHEMIA
    Abstract: The formation of signal-promoting dimeric or oligomeric receptor complexes at the cell surface is modulated by self-interaction of their transmembrane (TM) domains. To address the importance of TM domain packing density for receptor functionality, we examined a set of asparagine mutants in the TM domain of the erythropoietin receptor (EpoR). We identified EpoR-T242N as a receptor variant that is present at the cell surface similar to wild-type EpoR but lacks visible localization in vesicle-like structures and is impaired in efficient activation of specific signaling cascades. Analysis by a molecular modeling approach indicated an increased interhelical distance for the EpoR-T242N TM dimer. By employing the model, we designed additional mutants with increased or decreased packing volume and confirmed a correlation between packing volume and biological responsiveness. These results propose that the packing density of the TM domain provides a novel layer for fine-tuned regulation of signal transduction and cellular decisions
    Type of Publication: Journal article published
    PubMed ID: 18855427
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