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  • CONFORMATIONAL SWITCH  (4)
Keywords
  • 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: RECEPTOR ; SPECTRA ; GENE ; PROTEINS ; BINDING ; BIOLOGY ; ELEMENTS ; STABILITY ; CD4-BINDING DOMAIN ; CONFORMATIONAL SWITCH ; GP120 ; FAMILIES ; POTENTIALS ; SET ; protein conformation ; CD-spectroscopy ; CHAIN INTERACTION INDEX ; conformational rigidity ; helix-inducing tetrads ; peptide folding ; switch peptides
    Abstract: In some naturally occurring protein sequences, an abrupt, concerted refolding from beta-sheet to helical conformation occurs when the polarity of the surrounding medium drops below a critical level. This switch-like behaviour was first observed on the HIV-1 envelope glycoprotein gp120, where it plays a crucial role in the efficient binding of gp120 to the T-cell receptor CD4. Previous work had shown that an N-terminal amino acid tetrad LPCR and a Trp located 5-20 residues downstream to the tetrad are common motifs in polarity-driven switch peptides. The LPCR tetrad governs the folding of the subsequent residues and acts as a helix initiation site, whereas the Trp is responsible for the cooperative character of the structural change due to multiple, simultaneous interactions of its quadrupole moment with several amino acid residues within the sequences. Here we identify and characterize new families of switch peptides that use different, turn-probable tetrads (LPST and VPSR) as helix initiation sites at the N-terminus. We have also been able to demonstrate that some tetrads with extremely high turn probability do not serve as helix initiation sites. Comparison of these with LPCR and the newly discovered tetrads LPST and VPSR has allowed a more comprehensive description of the physico-chemical properties of helix-inducing tetrads. The deeper understanding of the intrinsic properties of switch sequences allows the design of artificial polarity-driven switches, applicable in engineering of, e. g. controllable binding sites in artificial proteins.
    Type of Publication: Journal article published
    PubMed ID: 20878680
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  • 3
    Keywords: ENERGIES ; PEPTIDE ; Germany ; LINES ; DOMAIN ; IONS ; BINDING ; SEQUENCE ; ACID ; ACIDS ; ENERGY ; BEHAVIOR ; CONFORMATIONAL SWITCH ; GP120 ; HIV-1 ; CHAIN ; RE ; interaction ; HIV ; SWITCH ; USA ; POLARITY ; GAUSSIAN-BASIS SETS ; MEDIA ; ATOMS LI ; interactions ; amino acids ; POSITION ; APPROXIMATE COULOMB POTENTIALS ; AUXILIARY BASIS-SETS ; KR ; PI INTERACTIONS
    Abstract: A 15-residue sequence (LPCRIKQFINMWQEV) forming the principal CD4-binding domain of gp120 from HIV 1 displays unusual, highly cooperative refolding from beta-hairpin to 3(10) helix when the polarity of the surrounding medium drops below a critical point, the so-called conformational switch. The tryptophan at position 12 has been shown to be essential for the cooperativity of the refolding process, and several lines of evidence from earlier work had suggested that it was the aromatic quadrupole that was responsible for this. To de. ne more precisely what physico-chemical properties of tryptophan brought about the unique behavior of this peptide, nonproteogenic aromatic amino acids have been selected based on desired alterations in quadrupole moment, electrostatic potential surface, and binding energy to ions. These were built into the peptide in the place of tryptophan and their effect on switch behavior examined. It could be shown that a minimal strength of the quadrupole moment is necessary but not sufficient to enforce cooperativity of refolding, with other properties of tryptophan playing a role in the optimum interaction of this residue with other side chains of the peptide
    Type of Publication: Journal article published
    PubMed ID: 18599633
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  • 4
    Keywords: PROTEINS ; TYPE-1 ; HUMAN-IMMUNODEFICIENCY-VIRUS ; CONFORMATIONAL SWITCH ; MOLECULAR-DYNAMICS ; CD4-BINDING DOMAIN
    Abstract: A 15-residue segment within the principal CD4 binding domain of gp120 from HIV1 is a natural subject for vaccine development. Knowledge of a three-dimensional structure of this peptide in aqueous solution can in principle be used for pharmacophoric footprint identification. However, the peptide is resistant to structural characterization using nuclear magnetic resonance (NMR) due to aggregation properties. Here we examine the conformational properties of the peptide using molecular dynamics simulation. Three simulations were performed starting from widely different structures of the peptide determined by NMR in organic solvents. The three structures converge during the simulations to a common structure in both Cartesian and in backbone dihedral conformational space. Preliminary examination of the average three-dimensional structure identifies, after sequence threading, characteristics of potential use as a pharmacophoric footprint.
    Type of Publication: Journal article published
    PubMed ID: 11855981
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