Molecular Dynamic Simulation of Wild Type and Mutants of the Polymorphic Amyloid NNQNTF Segments of Elk Prion: Structural Stability and Thermodynamic of Association

    Authors

    W. M. Berhanu;A. E. Masunov

    Comments

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    Abbreviated Journal Title

    Biopolymers

    Keywords

    amyloid fibril; amyloid polymorphism; molecular dynamic simulation; beta; sheet; aggregation; oligomer; steric zipper; molecular dynamic; simulations; cross-beta structure; binding free energy; MM-PBSA; RMSF; RMSD; elk prion segment of NNQNTF; FREE-ENERGY CALCULATIONS; CROSS-BETA-SPINE; A-BETA; PROTEIN AGGREGATION; FIBRIL FORMATION; BINDING-ENERGY; HYDROGEN-BONDS; PHYSICAL BASIS; PEPTIDE; OLIGOMERS; Biochemistry & Molecular Biology; Biophysics

    Abstract

    A hexapeptide with amino acid sequence NNQNTF from the elk prion protein forms amyloid fibrils. Here we use molecular dynamic simulations of the oligomers and their single point glycine mutants to study their stability. In an effort to probe the structural stability and association thermodynamic in a realistic environment, all wildtype of NNQNTF polymorphic forms with different size and their corresponding double layer 5 strands single point glycine mutants were subjected to a total of 500 ns of explicit-solvent molecular dynamics (MD) simulation. Our results show that the structural stability of the NNQNTF oligomers increases with increasing the number of beta-strands for double layers. Our results also demonstrated that hydrophobic interaction is the principle driving force to stabilize the adjacent beta-strands while the steric zipper is responsible for holding the neighboring beta-sheet layers together. We used MM-PBSA approach free energy calculations to determine the role of nonpolar effects, electrostatics and entropy in binding. Nonpolar effects remained consistently more favorable in wild type and mutants reinforcing the importance of hydrophobic effects in protein-protein binding. While entropy systematically opposed binding in all cases, there was no observed trend in the entropy difference between wildtype and glycine mutant. Free energy decomposition shows residues situated at the interface were found to make favorable contributions to the peptide-peptide association. The study of the wild type and mutants in an explicit solvent may provide valuable insight for amyloid aggregation inhibitor design efforts. (C) 2011 Wiley Periodicals, Inc. Biopolymers 95: 573-590, 2011.

    Journal Title

    Biopolymers

    Volume

    95

    Issue/Number

    9

    Publication Date

    1-1-2011

    Document Type

    Article

    Language

    English

    First Page

    573

    Last Page

    590

    WOS Identifier

    WOS:000292561300001

    ISSN

    0006-3525

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