Molecular Dynamics of Monomeric IAPP in Solution

Inhaltsverzeichnis (Table of Contents)

• Introduction
  • Islet Amyloid Polypeptide
    • Diabetes Mellitus Type II
    • Mutations and Homologues
    • IAPP Properties
      • IAPP Aggregation
      • Proline
  • Hydrational Water
  • Overview
  • Thesis Objectives
• Methods
  • Molecular Dynamics Simulation Methods in a Nutshell
  • Preparation of Initial Conformations
    • In vacuo hIAPP Simulations
    • Solvated Uncapped hIAPP
    • Solvated Amide Capped hIAPP
  • Scaling Charges
  • Software
    • Ramachandran Angles
    • Hydrogen Bond Definitions
    • Statistical Properties
      • Water box and Maximum Distance between Heavy Atoms
    • Data Crunching
      • Error Estimate
      • Savitzky-Golay Smoothing Filter
      • Scott’s Choice
      • Rounding Data - Taylor
    • Hydration Water
      • System Description
      • Water Shell Analysis Software
  • Preparation of the Initial Conformations
    • Random Conformations from Vacuum
      • Data Analysis
        • Initial Modeled α-Helix Conformation
        • Comparison of Independent Starting Conformations
        • Independent Concatenated Data
    • Extended Trajectories
    • Conclusions
  • Water Percolation
    • Hydration Water Properties
    • Hydration Water Analysis
      • Temperature-Induced Percolation Transition of Hydration Water
      • Effect of the Spanning Water Network on Peptide Properties
      • Effect of Peptide Structure on the Spanning Network of Hydration Water
    • Conclusions
  • Comparing hIAPP and rIAPP in Liquid Water
    • Conformational Changes of Oxidized hIAPP at 330 K
      • Conformational Properties Rg, reted, and SASA of IAPP
    • Compact hIAPP Conformation at 330 K
      • Aromatic-Aromatic Interactions
      • Secondary Structure
        • Ramachandran Angles
        • DSSPcont
      • Snapshots of IAPP
      • H-bond Patterns and Secondary Structure of Oxidized hIAPP at 330 K
      • System Perturbation
        • Thermal Induced “Unfolding”
        • In silico Point Mutations on Oxidized hIAPP at 330 K
    • Discussion and Conclusions
      • Compact, but not Entirely Disordered, Polypeptide
      • Effect of P28 on the C-Terminal Region
      • Effect of Aromatic Residues
      • Temperature Effect on Oxidized hIAPP
      • Effect of the Disulfide Bond
  • Outlook

  Zielsetzung und Themenschwerpunkte (Objectives and Key Themes)

  : This dissertation aims to investigate the conformational properties of monomeric human and rat islet amyloid polypeptide (IAPP) in solution. The primary focus is on identifying structural differences between these two homologues that may contribute to the amyloidogenic behavior of human IAPP. Key themes explored in this research include:
  • The impact of proline residues on the conformation of IAPP, particularly the role of proline at position 28 in rat IAPP, which is known to inhibit amyloid formation.
  • The influence of aromatic residues on IAPP conformation, particularly the interactions between tyrosine and phenylalanine residues in human IAPP.
  • The role of the disulfide bond between cysteine residues in human IAPP in stabilizing compact conformations and promoting aggregation.
  • The effect of temperature on the conformational flexibility of IAPP, particularly the relationship between temperature and the formation of β-structures.
  • The influence of hydration water on the conformational dynamics of IAPP, particularly the break of the spanning hydration water network at around 320 K and its impact on the aggregation process.

  Zusammenfassung der Kapitel (Chapter Summaries)

  : Chapter 1 introduces the reader to the study of islet amyloid polypeptide (IAPP), a 37-amino acid peptide involved in the pathogenesis of type II diabetes. It discusses the properties of IAPP, including its aggregation behavior, the differences between human and rat IAPP sequences, and the importance of proline residues. Chapter 2 details the methods used in the study, primarily molecular dynamics (MD) simulations using the GROMACS software suite. Chapter 3 describes the preparation of initial conformations for the MD simulations, focusing on the challenge of creating representative starting structures for a natively unstructured peptide like IAPP. Chapter 4 investigates the properties of hydration water at the surface of IAPP and demonstrates a temperature-induced break of the spanning hydrogen-bonded network. Chapter 5 compares the conformational properties of human and rat IAPP in liquid water, highlighting the differences in flexibility, secondary structure, and the presence of specific interactions between residues.

  Schlüsselwörter (Keywords)

  : Islet amyloid polypeptide (IAPP), amyloidogenesis, molecular dynamics (MD) simulations, con�formational properties, proline, aromatic residues, disulfide bond, hydration water, percolation transition, aggregation.

  Frequently Asked Questions

  What is Islet Amyloid Polypeptide (IAPP)?

  Islet Amyloid Polypeptide (IAPP) is a 37-amino acid peptide involved in the pathogenesis of type II diabetes, known for its ability to form amyloid aggregates.

  What are the main differences between human (hIAPP) and rat (rIAPP)?

  Human IAPP is amyloidogenic and prone to aggregation, while rat IAPP is non-amyloidogenic. This difference is largely attributed to specific amino acid variations, such as the serine-to-proline substitution at residue 28.

  How does temperature affect IAPP conformation in solution?

  The study found that temperatures between 310K and 330K delimit a water percolation transition. Above this transition, hIAPP reaches a more compact state with increased β-bridge formation in the C-terminal region.

  What role does proline 28 play in rat IAPP (rIAPP)?

  Proline at position 28 in rIAPP acts as a structural stabilizer that promotes helical conformations, which in turn inhibits the formation of β-bridges necessary for aggregation.

  Why are aromatic residues important in hIAPP aggregation?

  The research highlights that interactions between Tyrosine and Phenylalanine residues facilitate a two-step mechanism that leads to compact, aggregation-prone conformations in human IAPP.

  What simulation method was used in this research?

  The study utilized Molecular Dynamics (MD) simulations, specifically using the GROMACS software suite, to observe the conformational properties of the peptides at physiological temperatures.