Biomaterial Database

pH-dependent conformations of the amyloid beta(1-28) peptide fragment explored using molecular dynamics. 1995

K Kirshenbaum, and V Daggett

Department of Medicinal Chemistry, University of Washington, Seattle 98195, USA.

Molecular dynamics simulations were used to successfully reproduce the experimentally observed pH-dependent conformational behavior of a monomeric peptide in aqueous solution. Simulations were conducted at 298 K on a peptide corresponding to residues 1-28 of the amyloid beta-peptide [referred to as beta(1-28)], which is the primary component of the plaques associated with Alzheimer's disease. beta(1-28) was found to be entirely alpha-helical at low pH. Upon deprotonation of acidic residues at medium pH, helical structure was lost in the N-terminal region. At high pH, some secondary structure was recovered to yield two helices joined by a kink. These results are in good agreement with the NMR solution structure at low pH [Zagorski and Barrow (1992) Biochemistry 31, 5621-5631; Talafous et al. (1994) Biochemistry 33, 7788-7796] and CD and NMR evidence of an alpha-helix to beta-sheet transition at mid-range pH [Barrow et al. (1992) J. Mol. Biol. 225, 1075-1093]. Additional simulations were also able to regenerate folded species from partially unfolded conformers. A mechanism for the pH-dependent structural rearrangements is proposed that involves the creation of a hydrogen-bonded pair between Ser 8 and Glu 11. The evidence for the existence of a multiconformational equilibrium of folded and unfolded species of the peptide is discussed.

UI	MeSH Term	Description	Entries
D008958	Models, Molecular	Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.	Molecular Models,Model, Molecular,Molecular Model
D008969	Molecular Sequence Data	Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.	Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D009682	Magnetic Resonance Spectroscopy	Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (MAGNETIC RESONANCE IMAGING).	In Vivo NMR Spectroscopy,MR Spectroscopy,Magnetic Resonance,NMR Spectroscopy,NMR Spectroscopy, In Vivo,Nuclear Magnetic Resonance,Spectroscopy, Magnetic Resonance,Spectroscopy, NMR,Spectroscopy, Nuclear Magnetic Resonance,Magnetic Resonance Spectroscopies,Magnetic Resonance, Nuclear,NMR Spectroscopies,Resonance Spectroscopy, Magnetic,Resonance, Magnetic,Resonance, Nuclear Magnetic,Spectroscopies, NMR,Spectroscopy, MR
D010446	Peptide Fragments	Partial proteins formed by partial hydrolysis of complete proteins or generated through PROTEIN ENGINEERING techniques.	Peptide Fragment,Fragment, Peptide,Fragments, Peptide
D002942	Circular Dichroism	A change from planar to elliptic polarization when an initially plane-polarized light wave traverses an optically active medium. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)	Circular Dichroism, Vibrational,Dichroism, Circular,Vibrational Circular Dichroism
D003198	Computer Simulation	Computer-based representation of physical systems and phenomena such as chemical processes.	Computational Modeling,Computational Modelling,Computer Models,In silico Modeling,In silico Models,In silico Simulation,Models, Computer,Computerized Models,Computer Model,Computer Simulations,Computerized Model,In silico Model,Model, Computer,Model, Computerized,Model, In silico,Modeling, Computational,Modeling, In silico,Modelling, Computational,Simulation, Computer,Simulation, In silico,Simulations, Computer
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006863	Hydrogen-Ion Concentration	The normality of a solution with respect to HYDROGEN ions; H+. It is related to acidity measurements in most cases by pH	pH,Concentration, Hydrogen-Ion,Concentrations, Hydrogen-Ion,Hydrogen Ion Concentration,Hydrogen-Ion Concentrations
D000595	Amino Acid Sequence	The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.	Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D012996	Solutions	The homogeneous mixtures formed by the mixing of a solid, liquid, or gaseous substance (solute) with a liquid (the solvent), from which the dissolved substances can be recovered by physical processes. (From Grant & Hackh's Chemical Dictionary, 5th ed)	Solution