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Understanding Protein/Peptide Self-Assembly using Structural and Biophysical Chemistry

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Physical Chemistry".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 54963

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Special Issue Editor

Dr. Veronica Dodero

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Guest Editor

Faculty of Chemistry, Bielefeld University, Bielefeld, Germany
Interests: peptide self-assembly; supramolecular chemistry; chemical biology; circular dichroism; gluten-related disorders; gliadin peptide oligomers; translational chemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Protein and peptide self-assembly is an emerging area of research at the triple point where chemistry, biology, and physics meet.
Protein self-assembly makes up functional superstructures in living cells. These organized three-dimensional nano- and microstructures are built up by the information encoded in single amino acids and tuned by environmental stimuli. It is also accepted that misfolding and self-assembly of proteins and peptides into more complex supramolecular structures such as amyloid oligomers, protofilaments, and fibrils are associated with different pathogenesis like prion or Alzheimer’s diseases, among others. Finally, the secondary transition and self-assembling of peptides into gels, fibrils, fibers, tubules, or sheets have found applications in tissue engineering and biomedical devices. In this context, the control of these functional biomaterials triggered by an external stimulus such as temperature, pH, or mechanical forces is highly desired.

The purpose of this Special Issue is to show the power of biophysical chemistry in combination with other areas of chemistry, like peptide chemistry, the design of sensors of peptide self-assembly, or molecular modeling to elucidate at the molecular level the process of self-assembly in proteins and peptides. Additionally, advances in understanding protein/peptide self-assembly from a soft matter perspective are particularly welcome, as well as multidisciplinary studies offering new principles, strategies, and insights. Contributions to this Special Issue, both in the form of original research or review articles that favor the advance of this fascinating area of research, are cordially invited.

Dr. Veronica Dodero
Guest Editor

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Keywords

Peptide design and self-assembly
Protein folding and quaternary structure evaluation
Microscopic/spectroscopic tools for the study of peptide self-assembly
Protein/peptide self-assembly at interfaces and in confinement
Amyloids in disease
Technological and biomedical applications of self-assembled peptides
Computational tools to elucidate protein/peptide self-assembly
New biophysical methodologies used in protein/peptide self-assembly
Soft matter and peptide self-assembly.

Published Papers (10 papers)

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Research

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18 pages, 3991 KiB

Open AccessFeature PaperArticle

Unraveling the Compositional and Molecular Features Involved in Lysozyme-Benzothiazole Derivative Interactions

by Ramón Rial, Michael González-Durruthy, Manuel Somoza, Zhen Liu and Juan M. Ruso

Molecules 2021, 26(19), 5855; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26195855 - 27 Sep 2021

Cited by 4 | Viewed by 1820

Abstract

In this work we present a computational analysis together with experimental studies, focusing on the interaction between a benzothiazole (BTS) and lysozyme. Results obtained from isothermal titration calorimetry, UV-vis, and fluorescence were contrasted and complemented with molecular docking and machine learning techniques. The free energy values obtained both experimentally and theoretically showed excellent similarity. Calorimetry, UV-vis, and 3D/2D-lig-plot analysis revealed that the most relevant interactions between BTS and lysozyme are based on a predominance of aromatic, hydrophobic Van der Waals interactions, mainly aromatic edge-to-face (T-shaped) π-π stacking interactions between the benzene ring belonging to the 2-(methylthio)-benzothiazole moiety of BTS and the aromatic amino acid residue TRP108 of the lysozyme receptor. Next, conventional hydrogen bonding interactions contribute to the stability of the BTS-lysozyme coupling complex. In addition, mechanistic approaches performed using elastic network models revealed that the BTS ligand theoretically induces propagation of allosteric signals, suggesting non-physiological conformational flexing in large blocks of lysozyme affecting α-helices. Likewise, the BTS ligand interacts directly with allosteric residues, inducing perturbations in the conformational dynamics expressed as a moderate conformational softening in the α-helices H1, H2, and their corresponding β-loop in the lysozyme receptor, in contrast to the unbound state of lysozyme. Full article

(This article belongs to the Special Issue Understanding Protein/Peptide Self-Assembly using Structural and Biophysical Chemistry)

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14 pages, 2515 KiB

Open AccessCommunication

Oligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicity

by Ana Frangolho, Bruno E. Correia, Daniela C. Vaz, Zaida L. Almeida and Rui M. M. Brito

Molecules 2020, 25(23), 5698; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25235698 - 03 Dec 2020

Cited by 10 | Viewed by 3056

Abstract

One of the molecular hallmarks of amyloidoses is ordered protein aggregation involving the initial formation of soluble protein oligomers that eventually grow into insoluble fibrils. The identification and characterization of molecular species critical for amyloid fibril formation and disease development have been the focus of intense analysis in the literature. Here, using photo-induced cross-linking of unmodified proteins (PICUP), we studied the early stages of oligomerization of human transthyretin (TTR), a plasma protein involved in amyloid diseases (ATTR amyloidosis) with multiple clinical manifestations. Upon comparison, the oligomerization processes of wild-type TTR (TTRwt) and several TTR variants (TTRV30M, TTRL55P, and TTRT119M) clearly show distinct oligomerization kinetics for the amyloidogenic variants but a similar oligomerization mechanism. The oligomerization kinetics of the TTR amyloidogenic variants under analysis showed a good correlation with their amyloidogenic potential, with the most amyloidogenic variants aggregating faster (TTRL55P > TTRV30M > TTRwt). Moreover, the early stage oligomerization mechanism for these variants involves stepwise addition of monomeric units to the growing oligomer. A completely different behavior was observed for the nonamyloidogenic TTRT119M variant, which does not form oligomers in the same acidic conditions and even for longer incubation times. Thorough characterization of the initial steps of TTR oligomerization is critical for better understanding the origin of ATTR cytotoxicity and developing novel therapeutic strategies for the treatment of ATTR amyloidosis. Full article

(This article belongs to the Special Issue Understanding Protein/Peptide Self-Assembly using Structural and Biophysical Chemistry)

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18 pages, 3052 KiB

Open AccessArticle

Synthesis and Characterization of Cholesteryl Conjugated Lysozyme (CHLysozyme)

by Shinji Katsura, Takayuki Furuishi, Haruhisa Ueda and Etsuo Yonemochi

Molecules 2020, 25(16), 3704; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25163704 - 14 Aug 2020

Cited by 2 | Viewed by 2188

Abstract

Hydrophobic interaction is important for protein conformation. Conjugation of a hydrophobic group can introduce intermolecular hydrophobic contacts that can be contained within the molecule. It is possible that a strongly folded state can be formed in solution compared with the native state. In this study, we synthesized cholesteryl conjugated lysozyme (CHLysozyme) using lysozyme and cholesterol as the model protein and hydrophobic group, respectively. Cholesteryl conjugation to lysozyme was confirmed by nuclear-magnetic resonance. Differential-scanning calorimetry suggested that CHLysozyme was folded in solution. CHLysozyme secondary structure was similar to lysozyme, although circular dichroism spectra indicated differences to the tertiary structure. Fluorescence measurements revealed a significant increase in the hydrophobic surface of CHLysozyme compared with that of lysozyme; CHLysozyme self-associated by hydrophobic interaction of the conjugated cholesterol but the hydrophobic surface of CHLysozyme decreased with time. The results suggested that hydrophobic interaction changed from intramolecular interaction to an intermolecular interaction. Furthermore, the relative activity of CHLysozyme to lysozyme increased with time. Therefore, CHLysozyme likely forms a folded state with an extended durability of activity. Moreover, lysozyme was denatured in 100% DMSO but the local environment of tryptophan in CHLysozyme was similar to that of a native lysozyme. Thus, this study suggests that protein solution stability and resistance to organic solvents may be improved by conjugation of a hydrophobic group. Full article

(This article belongs to the Special Issue Understanding Protein/Peptide Self-Assembly using Structural and Biophysical Chemistry)

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10 pages, 3907 KiB

Open AccessArticle

Characterization by Nano-Infrared Spectroscopy of Individual Aggregated Species of Amyloid Proteins

by Jehan Waeytens, Vincent Van Hemelryck, Ariane Deniset-Besseau, Jean-Marie Ruysschaert, Alexandre Dazzi and Vincent Raussens

Molecules 2020, 25(12), 2899; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25122899 - 24 Jun 2020

Cited by 26 | Viewed by 3394

Abstract

Amyloid fibrils are composed of aggregated peptides or proteins in a fibrillar structure with a higher β-sheet content than in their native structure. To characterize them, we used an innovative tool that coupled infrared spectroscopy with atomic force microscopy (AFM-IR). With this method, we show that we can detect different individual aggregated species from oligomers to fibrils and study their morphologies by AFM and their secondary structures based on their IR spectra. AFM-IR overcomes the weak spatial resolution of usual infrared spectroscopy and achieves a resolution of ten nanometers, the size of isolated fibrils. We characterized oligomers, amyloid fibrils of Aβ42 and fibrils of α-synuclein. To our surprise, we figured out that the nature of some surfaces (ZnSe) used to study the samples induces destructuring of amyloid samples, leading to amorphous aggregates. We strongly suggest taking this into consideration in future experiments with amyloid fibrils. More importantly, we demonstrate the advantages of AFM-IR, with a high spatial resolution (≤ 10 nm) allowing spectrum recording on individual aggregated supramolecular entities selected thanks to the AFM images or on thin layers of proteins. Full article

(This article belongs to the Special Issue Understanding Protein/Peptide Self-Assembly using Structural and Biophysical Chemistry)

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Review

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26 pages, 2737 KiB

Open AccessReview

Amyloid Cross-Seeding: Mechanism, Implication, and Inhibition

by Sushma Subedi, Santanu Sasidharan, Niharika Nag, Prakash Saudagar and Timir Tripathi

Molecules 2022, 27(6), 1776; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27061776 - 08 Mar 2022

Cited by 34 | Viewed by 4806

Abstract

Most neurodegenerative diseases such as Alzheimer’s disease, type 2 diabetes, Parkinson’s disease, etc. are caused by inclusions and plaques containing misfolded protein aggregates. These protein aggregates are essentially formed by the interactions of either the same (homologous) or different (heterologous) sequences. Several experimental pieces of evidence have revealed the presence of cross-seeding in amyloid proteins, which results in a multicomponent assembly; however, the molecular and structural details remain less explored. Here, we discuss the amyloid proteins and the cross-seeding phenomena in detail. Data suggest that targeting the common epitope of the interacting amyloid proteins may be a better therapeutic option than targeting only one species. We also examine the dual inhibitors that target the amyloid proteins participating in the cross-seeding events. The future scopes and major challenges in understanding the mechanism and developing therapeutics are also considered. Detailed knowledge of the amyloid cross-seeding will stimulate further research in the practical aspects and better designing anti-amyloid therapeutics. Full article

(This article belongs to the Special Issue Understanding Protein/Peptide Self-Assembly using Structural and Biophysical Chemistry)

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21 pages, 2664 KiB

Open AccessReview

Implementing Complementary Approaches to Shape the Mechanism of α-Synuclein Oligomerization as a Model of Amyloid Aggregation

by Marco Giampà, María J. Amundarain, Maria Georgina Herrera, Nicolò Tonali and Veronica I. Dodero

Molecules 2022, 27(1), 88; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27010088 - 24 Dec 2021

Cited by 7 | Viewed by 3597

Abstract

The aggregation of proteins into amyloid fibers is linked to more than forty still incurable cellular and neurodegenerative diseases such as Parkinson’s disease (PD), multiple system atrophy, Alzheimer’s disease and type 2 diabetes, among others. The process of amyloid formation is a main feature of cell degeneration and disease pathogenesis. Despite being methodologically challenging, a complete understanding of the molecular mechanism of aggregation, especially in the early stages, is essential to find new biological targets for innovative therapies. Here, we reviewed selected examples on α-syn showing how complementary approaches, which employ different biophysical techniques and models, can better deal with a comprehensive study of amyloid aggregation. In addition to the monomer aggregation and conformational transition hypothesis, we reported new emerging theories regarding the self-aggregation of α-syn, such as the alpha-helix rich tetramer hypothesis, whose destabilization induce monomer aggregation; and the liquid-liquid phase separation hypothesis, which considers a phase separation of α-syn into liquid droplets as a primary event towards the evolution to aggregates. The final aim of this review is to show how multimodal methodologies provide a complete portrait of α-syn oligomerization and can be successfully extended to other protein aggregation diseases. Full article

(This article belongs to the Special Issue Understanding Protein/Peptide Self-Assembly using Structural and Biophysical Chemistry)

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17 pages, 2930 KiB

Open AccessReview

Insight to Functional Conformation and Noncovalent Interactions of Protein-Protein Assembly Using MALDI Mass Spectrometry

by Marco Giampà and Elvira Sgobba

Molecules 2020, 25(21), 4979; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25214979 - 28 Oct 2020

Cited by 10 | Viewed by 4241

Abstract

Noncovalent interactions are the keys to the structural organization of biomolecule e.g., proteins, glycans, lipids in the process of molecular recognition processes e.g., enzyme-substrate, antigen-antibody. Protein interactions lead to conformational changes, which dictate the functionality of that protein-protein complex. Besides biophysics techniques, noncovalent interaction and conformational dynamics, can be studied via mass spectrometry (MS), which represents a powerful tool, due to its low sample consumption, high sensitivity, and label-free sample. In this review, the focus will be placed on Matrix-Assisted Laser Desorption Ionization Mass Spectrometry (MALDI-MS) and its role in the analysis of protein-protein noncovalent assemblies exploring the relationship within noncovalent interaction, conformation, and biological function. Full article

(This article belongs to the Special Issue Understanding Protein/Peptide Self-Assembly using Structural and Biophysical Chemistry)

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35 pages, 3981 KiB

Open AccessReview

Evaluation of Peptide/Protein Self-Assembly and Aggregation by Spectroscopic Methods

by María Florencia Pignataro, María Georgina Herrera and Verónica Isabel Dodero

Molecules 2020, 25(20), 4854; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25204854 - 21 Oct 2020

Cited by 89 | Viewed by 18972

Abstract

The self-assembly of proteins is an essential process for a variety of cellular functions including cell respiration, mobility and division. On the other hand, protein or peptide misfolding and aggregation is related to the development of Parkinson’s disease and Alzheimer’s disease, among other aggregopathies. As a consequence, significant research efforts are directed towards the understanding of this process. In this review, we are focused on the use of UV-Visible Absorption Spectroscopy, Fluorescence Spectroscopy and Circular Dichroism to evaluate the self-organization of proteins and peptides in solution. These spectroscopic techniques are commonly available in most chemistry and biochemistry research laboratories, and together they are a powerful approach for initial as well as routine evaluation of protein and peptide self-assembly and aggregation under different environmental stimulus. Furthermore, these spectroscopic techniques are even suitable for studying complex systems like those in the food industry or pharmaceutical formulations, providing an overall idea of the folding, self-assembly, and aggregation processes, which is challenging to obtain with high-resolution methods. Here, we compiled and discussed selected examples, together with our results and those that helped us better to understand the process of protein and peptide aggregation. We put particular emphasis on the basic description of the methods as well as on the experimental considerations needed to obtain meaningful information, to help those who are just getting into this exciting area of research. Moreover, this review is particularly useful to those out of the field who would like to improve reproducibility in their cellular and biomedical experiments, especially while working with peptide and protein systems as an external stimulus. Our final aim is to show the power of these low-resolution techniques to improve our understanding of the self-assembly of peptides and proteins and translate this fundamental knowledge in biomedical research or food applications. Full article

(This article belongs to the Special Issue Understanding Protein/Peptide Self-Assembly using Structural and Biophysical Chemistry)

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69 pages, 26102 KiB

Open AccessReview

The Diverse World of Foldamers: Endless Possibilities of Self-Assembly

by Samuele Rinaldi

Molecules 2020, 25(14), 3276; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25143276 - 18 Jul 2020

Cited by 37 | Viewed by 6238

Abstract

Different classes of foldamers, which are synthetic oligomers that adopt well-defined conformations in solution, have been the subject of extensive studies devoted to the elucidation of the forces driving their secondary structures and their potential as bioactive molecules. Regardless of the backbone type (peptidic or abiotic), the most important features of foldamers are the high stability, easy predictability and tunability of their folding, as well as the possibility to endow them with enhanced biological functions, with respect to their natural counterparts, by the correct choice of monomers. Foldamers have also recently started playing a starring role in the self-assembly of higher-order structures. In this review, selected articles will be analyzed to show the striking number of self-assemblies obtained for foldamers with different backbones, which will be analyzed in order of increasing complexity. Starting from the simplest self-associations in solution (e.g., dimers of β-strands or helices, bundles, interpenetrating double and multiple helices), the formation of monolayers, vesicles, fibers, and eventually nanostructured solid tridimensional morphologies will be subsequently described. The experimental techniques used in the structural investigation, and in the determination of the driving forces and mechanisms underlying the self-assemblies, will be systematically reported. Where applicable, examples of biomimetic self-assembled foldamers and their interactions with biological components will be described. Full article

(This article belongs to the Special Issue Understanding Protein/Peptide Self-Assembly using Structural and Biophysical Chemistry)

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33 pages, 4702 KiB

Open AccessReview

The Positive Side of the Alzheimer’s Disease Amyloid Cross-Interactions: The Case of the Aβ 1-42 Peptide with Tau, TTR, CysC, and ApoA1

by Lidia Ciccone, Chenghui Shi, Davide di Lorenzo, Anne-Cécile Van Baelen and Nicolo Tonali

Molecules 2020, 25(10), 2439; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25102439 - 23 May 2020

Cited by 38 | Viewed by 5414

Abstract

Alzheimer’s disease (AD) represents a progressive amyloidogenic disorder whose advancement is widely recognized to be connected to amyloid-β peptides and Tau aggregation. However, several other processes likely contribute to the development of AD and some of them might be related to protein-protein interactions. Amyloid aggregates usually contain not only single type of amyloid protein, but also other type of proteins and this phenomenon can be rationally explained by the process of protein cross-seeding and co-assembly. Amyloid cross-interaction is ubiquitous in amyloid fibril formation and so a better knowledge of the amyloid interactome could help to further understand the mechanisms of amyloid related diseases. In this review, we discuss about the cross-interactions of amyloid-β peptides, and in particular Aβ1-42, with other amyloids, which have been presented either as integrated part of Aβ neurotoxicity process (such as Tau) or conversely with a preventive role in AD pathogenesis by directly binding to Aβ (such as transthyretin, cystatin C and apolipoprotein A1). Particularly, we will focus on all the possible therapeutic strategies aiming to rescue the Aβ toxicity by taking inspiration from these protein-protein interactions. Full article

(This article belongs to the Special Issue Understanding Protein/Peptide Self-Assembly using Structural and Biophysical Chemistry)

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