Multiscale Molecular Simulations of Cross-sequence Interactions Between Amyloid Peptides PDF Download
Are you looking for read ebook online? Search for your book and save it on your Kindle device, PC, phones or tablets. Download Multiscale Molecular Simulations of Cross-sequence Interactions Between Amyloid Peptides PDF full book. Access full book title Multiscale Molecular Simulations of Cross-sequence Interactions Between Amyloid Peptides by Mingzhen Zhang. Download full books in PDF and EPUB format.
Author: Mingzhen Zhang
Publisher:
ISBN:
Category : Aggregation (Chemistry)
Languages : en
Pages : 195
Get Book Here
Book Description
Amyloid aggregation have been implicated in the pathology of many neurodegenerative diseases, including prion disease, Alzheimer's disease (AD), type II diabetes (T2D), and Parkinson disease. Amyloid peptides undergo the nucleation-polymerization aggregation process, during which amyloid peptides experience structural conversions from unstructured monomers to critical nucleus, and eventually to amyloid fibrils containing dominant ß-sheet structures. Such common misfolding and aggregation characteristics, in some cases, drive cross-seeding interactions between amyloid peptides, which play a major role in the progression and transmission between the neurodegenerative diseases. In the experiments, the cross-seeding interactions between amyloid peptides including ß-amyloid (Aß)-islet amyloid peptides (IAPP), Aß-tau, Aß-prion, human IAPP-rat IAPP, and tau-synuclein amyloids have been extensively implicated. However, high-resolution evidence is still unavailable and little is known about how these two peptides interact with each other. In our research, we perform the multiscale molecular simulations to sysmetically study the cross-seeding interactions between different amyloid peptides at the atomic resolution, with the particular focus on the prediction of the atomic structures, the dynamic behavious in bulk and membrane enviroment, and the interface properties of the hIAPP-rIAPP and Aß-hIAPP cross-seeding assemblies. In Chapter I and II, we model and simulate different heteroassemblies formed by the amyloidogenic hIAPP and the nonamyloidogenic rIAPP peptides. The U-shaped hIAPP monomers and oligomers can interact with conformationally similar rIAPP to form stable complexes and to co-assemble into heterogeneous structures via the interfacial hydrogen bonds and hydrophobic contacts at ß-sheet regions. This work demonstrates the existence of cross-interactions between the two different IAPP peptides at the atomic level, providing an improved fundamental understanding of the cross-seeding of different amyloid sequences towards amyloid aggregation and toxicity mechanisms. In Chapter III, IV and V, we investigate the cross-seeding interactions between Aß and hIAPP using a combination of coarse-grained (CG) replica-exchange molecular dynamics (REMD), all-atom molecular dynamics (MD) simulations and Markov Chain Monte Carlo (MCMC) simulations. We for the first time obtain the full free energy landscape for Aß-hIAPP cross-seeding interactions, by which the atomic structure of Aß-hIAPP cross-seeding assembly is determined. Computational mutagenesis studies reveal that disruption of interfacial salt bridges largely disfavor the ß-sheet-to-ß-sheet association, highlighting the importance of salt bridges in the formation of cross-seeding assemblies. We also probe the behaviors of Aß-hIAPP cross-seeding assemblies on zwitterionic POPC and anionic POPC/POPG membranes, determining the specific orientations and demonstrating that electrostatic interactions are the major forces governing peptide-lipid interactions. This work confirms the cross-seeding interactions between Aß and hIAPP, explaining the potential pathological link between AD and T2D. The atomic insights into the cross-seeding intearctions between amyloid peptides obtained from this work are expected to improve the understanding of the amyloid peptides and inspire the peptide inhibitor design towards the neurodegenerative diseases.
Author: Mingzhen Zhang
Publisher:
ISBN:
Category : Aggregation (Chemistry)
Languages : en
Pages : 195
Get Book Here
Book Description
Amyloid aggregation have been implicated in the pathology of many neurodegenerative diseases, including prion disease, Alzheimer's disease (AD), type II diabetes (T2D), and Parkinson disease. Amyloid peptides undergo the nucleation-polymerization aggregation process, during which amyloid peptides experience structural conversions from unstructured monomers to critical nucleus, and eventually to amyloid fibrils containing dominant ß-sheet structures. Such common misfolding and aggregation characteristics, in some cases, drive cross-seeding interactions between amyloid peptides, which play a major role in the progression and transmission between the neurodegenerative diseases. In the experiments, the cross-seeding interactions between amyloid peptides including ß-amyloid (Aß)-islet amyloid peptides (IAPP), Aß-tau, Aß-prion, human IAPP-rat IAPP, and tau-synuclein amyloids have been extensively implicated. However, high-resolution evidence is still unavailable and little is known about how these two peptides interact with each other. In our research, we perform the multiscale molecular simulations to sysmetically study the cross-seeding interactions between different amyloid peptides at the atomic resolution, with the particular focus on the prediction of the atomic structures, the dynamic behavious in bulk and membrane enviroment, and the interface properties of the hIAPP-rIAPP and Aß-hIAPP cross-seeding assemblies. In Chapter I and II, we model and simulate different heteroassemblies formed by the amyloidogenic hIAPP and the nonamyloidogenic rIAPP peptides. The U-shaped hIAPP monomers and oligomers can interact with conformationally similar rIAPP to form stable complexes and to co-assemble into heterogeneous structures via the interfacial hydrogen bonds and hydrophobic contacts at ß-sheet regions. This work demonstrates the existence of cross-interactions between the two different IAPP peptides at the atomic level, providing an improved fundamental understanding of the cross-seeding of different amyloid sequences towards amyloid aggregation and toxicity mechanisms. In Chapter III, IV and V, we investigate the cross-seeding interactions between Aß and hIAPP using a combination of coarse-grained (CG) replica-exchange molecular dynamics (REMD), all-atom molecular dynamics (MD) simulations and Markov Chain Monte Carlo (MCMC) simulations. We for the first time obtain the full free energy landscape for Aß-hIAPP cross-seeding interactions, by which the atomic structure of Aß-hIAPP cross-seeding assembly is determined. Computational mutagenesis studies reveal that disruption of interfacial salt bridges largely disfavor the ß-sheet-to-ß-sheet association, highlighting the importance of salt bridges in the formation of cross-seeding assemblies. We also probe the behaviors of Aß-hIAPP cross-seeding assemblies on zwitterionic POPC and anionic POPC/POPG membranes, determining the specific orientations and demonstrating that electrostatic interactions are the major forces governing peptide-lipid interactions. This work confirms the cross-seeding interactions between Aß and hIAPP, explaining the potential pathological link between AD and T2D. The atomic insights into the cross-seeding intearctions between amyloid peptides obtained from this work are expected to improve the understanding of the amyloid peptides and inspire the peptide inhibitor design towards the neurodegenerative diseases.
Author: Jun Zhao
Publisher:
ISBN:
Category : Amyloid
Languages : en
Pages : 280
Get Book Here
Book Description
Biological membranes function as an essential barrier between living cells and their environments. The membrane associated peptides (MAPs) interact with membrane either to facilitate the molecules exchange between the environments and cytoplasm (e.g. cell-penetrating peptide), or to disturb the membrane (e.g. amyloid peptides and antimicrobial peptides). The structures and activity of these peptides are essential to understand the mechanisms and to screen the drug candidates. Thus, in this dissertation, the structure prediction and screening of MAPs were firstly performed in Chapter II, III, and IV. We developed a structures-screening program base on GBMV implicit-solvent evaluation and a structure population evaluation program by Monte Carlo simulation to search the aggregated structures of amyloid peptide hIAPP with dominant populations. Seven stacking-sandwich models and three the wrapping-cord models were determined, which can also serve as templates to present double- and triple-stranded helical fibrils via peptide elongation, explaining the polymorphism of amyloid oligomers and fibrils. Base on the predicted oligomeric structures, the mechanisms of amyloid toxicity can be studied. We further investigated the dynamic structures, ion conductivity, and membrane interactions of hIAPP pores in the DOPC bilayer using molecular dynamics simulations (Chapter V and VI). Our results suggested that loosely-associated [Beta]-structure motifs can be a general feature of toxic, unregulated channels. The process how MAPs adsorb on membrane and further penetrate across the membrane was futher evaluated by the transmembrane potential mean force (PMF). We constructed an effect platform including adaptive biasing force (ABF) method which accelerates the membrane penetration process, umbrella sampling method which effectively generates trans-membrane PMFs, and MARTINI coarse-grained force field to measure the free energy required to transfer the MAPs from bulk water phase to water-membrane interface, and further to bilayer interior (Chapter VII). The results implied that biological activity of antimicrobial peptides appeared to be closely related to their trans-membrane ability indicated by the PMF profiles. Moreover, due to the complicated components of cell membrane, it is better to simplify the interactions between MAP-membrane to MAP-artificial surfaces. Thus, in the last part of the dissertation, we further presented a series of exploratory molecular dynamics (MD) simulations to study the early adsorption and conformational change of amyloid peptide [Amyloid-beta] oligomers from dimer to hexamer on three different self-assembled monolayers (SAMs) (Chapter VIII). Within the timescale of MD simulations, the conformation, orientation, and adsorption of [Amyloid-beta] oligomers on the SAMs was determined by complex interplay among the size of [Amyloid-beta] oligomers, the surface chemistry of the SAMs, and the structure and dynamics of interfacial waters.
Author: Workalemahu Mikre Berhanu
Publisher:
ISBN:
Category : Amyloid
Languages : en
Pages : 227
Get Book Here
Book Description
Amyloids are highly ordered cross-[Greek lowercase letter beta] sheet aggregates that are associated with many diseases such as Alzheimer's, type II diabetes and prion diseases. Recently a progress has been made in structure elucidation, environmental effects and thermodynamic properties of amyloid aggregates. However, detailed understanding of how mutation, packing polymorphism and small organic molecules influence amyloid structure and dynamics is still lacking. Atomistic modeling of these phenomena with molecular dynamics (MD) simulations holds a great promise to bridge this gap. This Thesis describes the results of MD simulations, which provide insight into the effects of mutation, packing polymorphism and molecular inhibitors on amyloid peptides aggregation. Chapter 1 discusses the structure of amyloid peptides, diseases associated with amyloid aggregation, mechanism of aggregation and strategies to treat amyloid diseases. Chapter 2 describes the basic principles of molecular dynamic simulation and methods of trajectory analysis used in the Thesis. Chapter 3 presents the results of the study of several all-atom molecular dynamics simulations with explicit solvent, starting from the crystalline fragments of two to ten monomers each. Three different hexapeptides and their analogs produced with single glycine replacement were investigated to study the structural stability, aggregation behavior and thermodynamics of the amyloid oligomers. Chapter 4 presents multiple molecular dynamics (MD) simulation of a pair polymorphic form of five short segments of amyloid peptide. Chapter 5 describes MD study of single-layer oligomers of the full-length insulin with a goal to identify the structural elements that are important for insulin amyloid stability, and to suggest single glycine mutants that may improve formulation. Chapter 6 presents the investigation of the mechanism of the interaction of polyphenols molecules with the protofibrils formed by an amyloidogenic hexapeptide fragment (VQIVYK) of Tau peptide by molecular dynamics simulations in explicit solvent. We analyzed the trajectories of the large (7x4) aggregate with and without the polyphenols. Our MD simulations for both the short and full length amyloids revealed adding strands enhances the internal stability of wildtype aggregates. The degree of structural similarity between the oligomers in simulation and the fibril models constructed based on experimental data may explain why adding oligomers shortens the experimentally observed nucleation lag phase of amyloid aggregation. The MM-PBSA free energy calculation revealed nonpolar components of the free energy is more favorable while electrostatic solvation is unfavorable for the sheet to sheet interaction. This explains the acceleration of aggregation by adding nonpolar co-solvents (methanol, trifluoroethanol, and hexafluoroisopropanol). Free energy decomposition shows residues situated at the interface were found to make favorable contribution to the peptide-peptide association. The results from the simulations might provide both the valuable insight for amyloid aggregation as well as assist in inhibitor design efforts. First, the simulation of the single glycine mutants at the steric zipper of the short segments of various pathological peptides indicates the intersheet steric zipper is important for amyloid stability. Mutation of the side chains at the dry steric zipper disrupts the sheet to sheet packing, making the aggregation unstable. Thus, designing new peptidomimetic inhibitors able to prevent the fibril formation based on the steric zipper motif of the oligomers, similar to the ones examined in this study may become a viable therapeutic strategy. The various steric zipper microcrystal structures of short amyloid segments could be used as a template to design aggregation inhibitor that can block growth of the aggregates. Modification of the steric zipper structure (structure based design) with a single amino acid changes, shuffling the sequences, N- methylation of peptide amide bonds to suppress hydrogen bonding ability of NH groups or replacement with D amino acid sequence that interact with the parent steric zipper could be used in computational search for the new inhibitors. Second, the polyphenols were found to interact with performed oligomer through hydrogen bonding and induce conformational change creating an altered aggregate. The conformational change disrupts the intermolecular amyloid contact remodeling the amyloid aggregate. The recently reported microcrystal structure of short segments of amyloid peptides with small organic molecules could serve as a pharamcophore for virtual screening of aggregation inhibitor using combined docking and MD simulation with possible enhancement of lead enrichment. Finally, our MD simulation of short segments of amyloids with steric zipper polymorphism showed the stability depends on both sequence and packing arrangements. The hydrophilic polar GNNQQNY and NNQNTF with interface containing large polar and/or aromatic side chains (Q/N) are more stable than steric zipper interfaces made of small or hydrophobic residues (SSTNVG, VQIVYK, and MVGGVV). The larger sheet to sheet interface of the dry steric zipper through polar Q/N rich side chains was found to holds the sheets together better than non Q/N rich short amyloid segments. The packing polymorphism could influence the structure based design of aggregation inhibitor and a combination of different aggregation inhibitors might be required to bind to various morphologic forms of the amyloid peptides.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages :
Get Book Here
Book Description
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 13
Get Book Here
Book Description
Chemical reagents targeting and controlling amyloidogenic peptides have received much attention for helping identify their roles in the pathogenesis of protein-misfolding disorders. In this paper, we report a novel strategy for redirecting amyloidogenic peptides into nontoxic, off-pathway aggregates, which utilizes redox properties of a small molecule (DMPD, N, N-dimethyl-p-phenylenediamine) to trigger covalent adduct formation with the peptide. In addition, for the first time, biochemical, biophysical, and molecular dynamics simulation studies have been performed to demonstrate a mechanistic understanding for such an interaction between a small molecule (DMPD) and amyloid-[beta] (A[beta]) and its subsequent anti-amyloidogenic activity, which, upon its transformation, generates ligand-peptide adducts via primary amine-dependent intramolecular cross-linking correlated with structural compaction. Furthermore, in vivo efficacy of DMPD toward amyloid pathology and cognitive impairment was evaluated employing 5xFAD mice of Alzheimer's disease (AD). Such a small molecule (DMPD) is indicated to noticeably reduce the overall cerebral amyloid load of soluble A[beta] forms and amyloid deposits as well as significantly improve cognitive defects in the AD mouse model. Altogether our in vitro and in vivo studies of DMPD toward A[beta] with the first molecular-level mechanistic investigations present the feasibility of developing new, innovative approaches that employ redox-active compounds without the structural complexity as next-generation chemical tools for amyloid management.
Author: Ruhong Zhou
Publisher: CRC Press
ISBN: 1466562951
Category : Science
Languages : en
Pages : 392
Get Book Here
Book Description
Although molecular modeling has been around for a while, the groundbreaking advancement of massively parallel supercomputers and novel algorithms for parallelization is shaping this field into an exciting new area. Developments in molecular modeling from experimental and computational techniques have enabled a wide range of biological applications. Responding to this renaissance, Molecular Modeling at the Atomic Scale: Methods and Applications in Quantitative Biology includes discussions of advanced techniques of molecular modeling and the latest research advancements in biomolecular applications from leading experts. The book begins with a brief introduction of major methods and applications, then covers the development of cutting-edge methods/algorithms, new polarizable force fields, and massively parallel computing techniques, followed by descriptions of how these novel techniques can be applied in various research areas in molecular biology. It also examines the self-assembly of biomacromolecules, including protein folding, RNA folding, amyloid peptide aggregation, and membrane lipid bilayer formation. Additional topics highlight biomolecular interactions, including protein interactions with DNA/RNA, membrane, ligands, and nanoparticles. Discussion of emerging topics in biomolecular modeling such as DNA sequencing with solid-state nanopores and biological water under nanoconfinement round out the coverage. This timely summary contains the perspectives of leading experts on this transformation in molecular biology and includes state-of-the-art examples of how molecular modeling approaches are being applied to critical questions in modern quantitative biology. It pulls together the latest research and applications of molecular modeling and real-world expertise that can boost your research and development of applications in this rapidly changing field.
Author: Maxim Ryadnov
Publisher: Royal Society of Chemistry
ISBN: 1788014057
Category : Science
Languages : en
Pages : 196
Get Book Here
Book Description
Synthetic biology combines science and engineering in order to design, build and test novel biological functions and systems. As with any multi-disciplinary field, there is a rapidly-growing body of literature concerning synthetic biology and locating the best information or identifying the hottest topics can be time-consuming. This volume captures the expanding primary literature in the form of critical and comprehensive reviews providing the reader with an authoritative digest of the latest developments in this emerging field. Each chapter strives to highlight the most recent findings in specific sub-areas and reviews research reports that were published over the last two to three years. Leading researchers draw material from both dedicated journals and broader sources, revising traditional concepts in light of emerging discoveries while keeping up with recent progress, making this an essential reference to any library supporting this research.
Author: Thimmaiah Govindaraju
Publisher: Royal Society of Chemistry
ISBN: 1839162740
Category : Medical
Languages : en
Pages : 531
Get Book Here
Book Description
Alzheimer’s disease is an increasingly common form of dementia and despite rising interest in discovery of novel treatments and investigation into aetiology, there are no currently approved treatments that directly tackle the causes of the condition. Due to its multifactorial pathogenesis, current treatments are directed against symptoms and even precise diagnosis remains difficult as the majority of cases are diagnosed symptomatically and usually confirmed only by autopsy. Alzheimer’s Disease: Recent Findings in Pathophysiology, Diagnostic and Therapeutic Modalities provides a comprehensive overview from aetiology and neurochemistry to diagnosis, evaluation and management of Alzheimer's disease, and latest therapeutic approaches. Intended to provide an introduction to all aspects of the disease and latest developments, this book is ideal for students, postgraduates and researchers in neurochemistry, neurological drug discovery and Alzheimer’s disease.
Author: Vladimir N Uversky
Publisher: Academic Press
ISBN: 0123978211
Category : Science
Languages : en
Pages : 556
Get Book Here
Book Description
Bio-Nanoimaging: Protein Misfolding & Aggregation provides a unique introduction to both novel and established nanoimaging techniques for visualization and characterization of misfolded and aggregated protein species. The book is divided into three sections covering: - Nanotechnology and nanoimaging technology, including cryoelectron microscopy of beta(2)-microglobulin, studying amyloidogensis by FRET; and scanning tunneling microscopy of protein deposits - Polymorphisms of protein misfolded and aggregated species, including fibrillar polymorphism, amyloid-like protofibrils, and insulin oligomers - Polymorphisms of misfolding and aggregation processes, including multiple pathways of lysozyme aggregation, misfolded intermediate of a PDZ domain, and micelle formation by human islet amyloid polypeptide Protein misfolding and aggregation is a fast-growing frontier in molecular medicine and protein chemistry. Related disorders include cataracts, arthritis, cystic fibrosis, late-onset diabetes mellitus, and numerous neurodegenerative diseases like Alzheimer's and Parkinson's. Nanoimaging technology has proved crucial in understanding protein-misfolding pathologies and in potential drug design aimed at the inhibition or reversal of protein aggregation. Using these technologies, researchers can monitor the aggregation process, visualize protein aggregates and analyze their properties. Provides practical examples of nanoimaging research from leading molecular biology, cell biology, protein chemistry, biotechnology, genetics, and pharmaceutical labs Includes over 200 color images to illustrate the power of various nanoimaging technologies Focuses on nanoimaging techniques applied to protein misfolding and aggregation in molecular medicine
Author:
Publisher: Academic Press
ISBN: 0128033274
Category : Science
Languages : en
Pages : 393
Get Book Here
Book Description
Current Topics in Membranes is targeted toward scientists and researchers in biochemistry and molecular and cellular biology, providing the necessary membrane research to assist them in discovering the current state of a particular field and in learning where that field is heading. This volume offers an up to date presentation of current knowledge in the field of Lipid Domains. Written by leading experts Contains original material, both textual and illustrative, that should become a very relevant reference material The material is presented in a very comprehensive manner Both researchers in the field and general readers should find relevant and up-to-date information
