Alternative packing modes leading to amyloid polymorphism in five fragments studied with molecular dynamics

    Authors

    W. M. Berhanu;A. E. Masunov

    Comments

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    Abbreviated Journal Title

    Biopolymers

    Keywords

    packing polymorphs; Q; N rich residues; sheet to sheet interface; H-bond; content; H-bond occupancy; MM-PBSA; main chain hydrogen bond and side; chain hydrogen bond; CROSS-BETA-SPINE; FREE-ENERGY CALCULATIONS; A-BETA; DIFFERENT; CONFORMATIONS; FIBRIL FORMATION; PROTEIN; SIMULATION; STABILITY; AGGREGATION; CONSTRAINTS; Biochemistry & Molecular Biology; Biophysics

    Abstract

    Amyloid aggregates have been implicated in the pathogenesis of diseases such as type 2 diabetes, Alzheimer's, Parkinson's, and prion disease. Recently determined microcrystal structures of several short peptide segments derived from fibril-forming proteins revealed coexistence of alternative aggregation modes (amyloid polymorphism) formed by the same segment. This polymorphism may help in understanding the influence of the side chain packing on the amyloid stability. Here we use molecular dynamics (MD) simulation to analyze the stability of five pairs of polar and nonpolar polymorphic oligomers. MD simulation shows polymorphs with steric zipper interface containing large polar and/or aromatic side chains (GNNQQNY, and NNQNTF) are more stable than steric zipper interfaces made of small or hydrophobic residues (SSTNGVG, VQIVYK, and MVGGVV). Several geometric analyses revealed that larger sheet to sheet interface of the dry steric zipper through polar Q/N rich side chains holds the sheets together. Mutant simulations (Q/N?G) show substitutions with glycine disrupt the steric zipper, leading to unstable oligomers. Stability of Q/N rich oligomers was found to result from the large average number of hydrogen bonds. The molecular mechanics PoissonBoltzmann surface area (MM/PBSA) method reports the nonpolar component of free energy to be favorable, while electrostatic solvation is unfavorable for beta-sheet association. Knowledge of structural properties of these fibrils might be useful for developing therapeutic agents against amyloidoses as well as for developing biomaterials. (C) 2011 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 98: 131144, 2012.

    Journal Title

    Biopolymers

    Volume

    98

    Issue/Number

    2

    Publication Date

    1-1-2012

    Document Type

    Article

    Language

    English

    First Page

    131

    Last Page

    144

    WOS Identifier

    WOS:000311339500006

    ISSN

    0006-3525

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