Conformational properties of the full-length human and rat islet amyloid polypeptide (amyloidogenic hIAPP and non-amyloidogenic rIAPP, respectively) were studied at physiological temperatures by MD simulations both for the cysteine and cystine moieties. By means of a temperature scan, it was found that 310K and 330K delimit the temperature at which the water percolation transition occurs, where the biological activity is highest, and were therefore chosen for observing the conformational properties of IAPP. At all temperatures studied, IAPP does not adopt a well-defined conformation and is essentially random-coil in solution, although transient helices appear forming along the peptide between residues 8 and 22, particularly in the reduced form. Above the water percolation transition, the reduced hIAPP moiety presents a considerably diminished helical content remaining unstructured, while the natural cystine moiety reaches a rather compact state, presenting a radius of gyration that is almost 10% smaller than what was measured for the other variants, and characterized by intrapeptide H-bonds that form many β-bridges in the C-terminal region. This compact conformation presents a short end-to-end distance and seems to form through the formation of β -sheet conformations in the C-terminal region with a minimization of the Tyr/Phe distances in a two-step mechanism. The non-aggregating rIAPP also presents transient helical conformations, with a particularly stable helix located in proximity of the C-terminal region, starting from residues L27 and P28. These MD simulations show that P28 in rIAPP influences the secondary structure of IAPP by stabilizing the peptide in helical conformations. When this helix is not present, the peptide presents bends or H-bonded turns at P28 that seem to inhibit the formation of the β-bridges seen in hIAPP. Conversely, hIAPP is highly disordered in the C-terminal region, presenting transient isolated β-strand conformations, particularly at higher temperatures and when the natural disulfide bond is present. Such conformational differences found in these simulations could be responsible for the different aggregational propensities of the two different homologues. The increased helicity in rIAPP induced by the serine-to-proline variation at residue 28 seems to be a plausible inhibitor of its aggregation. The specific position of P28 could be more relevant for inhibiting the aggregation than the intrinsic properties of proline alone.
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
- Islet Amyloid Polypeptide
- 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
- Data Analysis
- Extended Trajectories
- Conclusions
- Random Conformations from Vacuum
- 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
- Conformational Changes of Oxidized hIAPP at 330 K
- 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.
- Quote paper
- Maximilian Andrews (Author), 2011, Molecular Dynamics of Monomeric IAPP in Solution, Munich, GRIN Verlag, https://www.grin.com/document/196217
