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Folding and Design of α-Helical Proteins and Peptides: Theory Meets Nanomaterials, Biotechnology and Health

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Macromolecules".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 17896

Special Issue Editor

Prof. Dr. Michael Kokkinidis

E-Mail Website
Guest Editor
1. Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece
2. Department of Biology, University of Crete, Heraklion, Greece
Interests: structural biology; protein crystallography; protein engineering; circular dichroism

Special Issue Information

The most common secondary structure in globular proteins is the α-helix, frequently occurring in the form of specific structural motifs such as coiled-coils and helical bundles. Being associated with a variety of functions, oligomerization states and protein topologies, the helical folding motifs have opened new avenues for the design and engineering of bio-inspired protein- or peptide-based nanostructures and functional biomaterials. Although our limited understanding of protein folding/ misfolding and oligomerization frequently presents major barriers in the development of α-helical biomaterials, recent theoretical studies and experimental approaches are beginning to chart this new territory, leading to countless possibilities for functionalization and new nanomaterials.

The aim of this Special Issue is to gather folding studies of α-helical structural motifs along with rational design experiments and applications of protein-/peptide-based biomaterials. The authors are invited to submit manuscripts presenting theoretical, experimental and applied research. Both research and review articles are welcome. We hope that this Special Issue will stimulate further research in the areas of α-helical folding/misfolding and bio-inspired materials and catalyze increased collaboration at the interface of chemistry, physics and biology to decipher basic mechanisms and applications in Materials Science, Biotechnology and Health and Disease.

Prof. Dr. Michael Kokkinidis
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • α-helix
  • Coiled-coils
  • α-helical bundles
  • Protein folding
  • Protein misfolding
  • Protein/peptide design
  • Protein oligomerization
  • Bio-inspired materials
  • Materials science
  • Health and disease

Published Papers (6 papers)

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Research

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15 pages, 2458 KiB  
Article
Residue Folding Degree—Relationship to Secondary Structure Categories and Use as Collective Variable
by Vladimir Sladek, Ryuhei Harada and Yasuteru Shigeta
Int. J. Mol. Sci. 2021, 22(23), 13042; https://doi.org/10.3390/ijms222313042 - 2 Dec 2021
Cited by 3 | Viewed by 2466
Abstract
Recently, we have shown that the residue folding degree, a network-based measure of folded content in proteins, is able to capture backbone conformational transitions related to the formation of secondary structures in molecular dynamics (MD) simulations. In this work, we focus primarily on [...] Read more.
Recently, we have shown that the residue folding degree, a network-based measure of folded content in proteins, is able to capture backbone conformational transitions related to the formation of secondary structures in molecular dynamics (MD) simulations. In this work, we focus primarily on developing a collective variable (CV) for MD based on this residue-bound parameter to be able to trace the evolution of secondary structure in segments of the protein. We show that this CV can do just that and that the related energy profiles (potentials of mean force, PMF) and transition barriers are comparable to those found by others for particular events in the folding process of the model mini protein Trp-cage. Hence, we conclude that the relative segment folding degree (the newly proposed CV) is a computationally viable option to gain insight into the formation of secondary structures in protein dynamics. We also show that this CV can be directly used as a measure of the amount of α-helical content in a selected segment. Full article
(This article belongs to the Special Issue Folding and Design of α-Helical Proteins and Peptides: Theory Meets Nanomaterials, Biotechnology and Health)
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13 pages, 2134 KiB  
Article
State-Targeting Stabilization of Adenosine A2A Receptor by Fusing a Custom-Made De Novo Designed α-Helical Protein
by Masaya Mitsumoto, Kanna Sugaya, Kazuki Kazama, Ryosuke Nakano, Takahiro Kosugi, Takeshi Murata and Nobuyasu Koga
Int. J. Mol. Sci. 2021, 22(23), 12906; https://doi.org/10.3390/ijms222312906 - 29 Nov 2021
Cited by 2 | Viewed by 3849
Abstract
G-protein coupled receptors (GPCRs) are known for their low stability and large conformational changes upon transitions between multiple states. A widely used method for stabilizing these receptors is to make chimeric receptors by fusing soluble proteins (i.e., fusion partner proteins) into the intracellular [...] Read more.
G-protein coupled receptors (GPCRs) are known for their low stability and large conformational changes upon transitions between multiple states. A widely used method for stabilizing these receptors is to make chimeric receptors by fusing soluble proteins (i.e., fusion partner proteins) into the intracellular loop 3 (ICL3) connecting the transmembrane helices 5 and 6 (TM5 and TM6). However, this fusion approach requires experimental trial and error to identify appropriate soluble proteins, residue positions, and linker lengths for making the fusion. Moreover, this approach has not provided state-targeting stabilization of GPCRs. Here, to rationally stabilize a class A GPCR, adenosine A2A receptor (A2AR) in a target state, we carried out the custom-made de novo design of α-helical fusion partner proteins, which can fix the conformation of TM5 and TM6 to that in an inactive state of A2AR through straight helical connections without any kinks or intervening loops. The chimeric A2AR fused with one of the designs (FiX1) exhibited increased thermal stability. Moreover, compared with the wild type, the binding affinity of the chimera against the agonist NECA was significantly decreased, whereas that against the inverse agonist ZM241385 was similar, indicating that the inactive state was selectively stabilized. Our strategy contributes to the rational state-targeting stabilization of GPCRs. Full article
(This article belongs to the Special Issue Folding and Design of α-Helical Proteins and Peptides: Theory Meets Nanomaterials, Biotechnology and Health)
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18 pages, 1525 KiB  
Article
Residual Helicity at the Active Site of the Histidine Phosphocarrier, HPr, Modulates Binding Affinity to Its Natural Partners
by José L. Neira, David Ortega-Alarcón, Bruno Rizzuti, Martina Palomino-Schätzlein, Adrián Velázquez-Campoy and Alberto Falcó
Int. J. Mol. Sci. 2021, 22(19), 10805; https://doi.org/10.3390/ijms221910805 - 6 Oct 2021
Cited by 2 | Viewed by 1530
Abstract
The phosphoenolpyruvate-dependent phosphotransferase system (PTS) modulates the preferential use of sugars in bacteria. The first proteins in the cascade are common to all organisms (EI and HPr). The active site of HPr involves a histidine (His15) located immediately before the beginning of the [...] Read more.
The phosphoenolpyruvate-dependent phosphotransferase system (PTS) modulates the preferential use of sugars in bacteria. The first proteins in the cascade are common to all organisms (EI and HPr). The active site of HPr involves a histidine (His15) located immediately before the beginning of the first α-helix. The regulator of sigma D (Rsd) protein also binds to HPr. The region of HPr comprising residues Gly9-Ala30 (HPr9–30), involving the first α-helix (Ala16-Thr27) and the preceding active site loop, binds to both the N-terminal region of EI and intact Rsd. HPr9–30 is mainly disordered. We attempted to improve the affinity of HPr9–30 to both proteins by mutating its sequence to increase its helicity. We designed peptides that led to a marginally larger population in solution of the helical structure of HPr9–30. Molecular simulations also suggested a modest increment in the helical population of mutants, when compared to the wild-type. The mutants, however, were bound with a less favorable affinity than the wild-type to both the N-terminal of EI (EIN) or Rsd, as tested by isothermal titration calorimetry and fluorescence. Furthermore, mutants showed lower antibacterial properties against Staphylococcus aureus than the wild-type peptide. Therefore, we concluded that in HPr, a compromise between binding to its partners and residual structure at the active site must exist to carry out its function. Full article
(This article belongs to the Special Issue Folding and Design of α-Helical Proteins and Peptides: Theory Meets Nanomaterials, Biotechnology and Health)
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22 pages, 6502 KiB  
Article
Structure and Thermal Stability of wtRop and RM6 Proteins through All-Atom Molecular Dynamics Simulations and Experiments
by Maria Arnittali, Anastassia N. Rissanou, Maria Amprazi, Michael Kokkinidis and Vagelis Harmandaris
Int. J. Mol. Sci. 2021, 22(11), 5931; https://doi.org/10.3390/ijms22115931 - 31 May 2021
Cited by 7 | Viewed by 2945
Abstract
In the current work we study, via molecular simulations and experiments, the folding and stability of proteins from the tertiary motif of 4-α-helical bundles, a recurrent motif consisting of four amphipathic α-helices packed in a parallel or antiparallel fashion. The focus is on [...] Read more.
In the current work we study, via molecular simulations and experiments, the folding and stability of proteins from the tertiary motif of 4-α-helical bundles, a recurrent motif consisting of four amphipathic α-helices packed in a parallel or antiparallel fashion. The focus is on the role of the loop region in the structure and the properties of the wild-type Rop (wtRop) and RM6 proteins, exploring the key factors which can affect them, through all-atom molecular dynamics (MD) simulations and supporting by experimental findings. A detailed investigation of structural and conformational properties of wtRop and its RM6 loopless mutation is presented, which display different physical characteristics even in their native states. Then, the thermal stability of both proteins is explored showing RM6 as more thermostable than wtRop through all studied measures. Deviations from native structures are detected mostly in tails and loop regions and most flexible residues are indicated. Decrease of hydrogen bonds with the increase of temperature is observed, as well as reduction of hydrophobic contacts in both proteins. Experimental data from circular dichroism spectroscopy (CD), are also presented, highlighting the effect of temperature on the structural integrity of wtRop and RM6. The central goal of this study is to explore on the atomic level how a protein mutation can cause major changes in its physical properties, like its structural stability. Full article
(This article belongs to the Special Issue Folding and Design of α-Helical Proteins and Peptides: Theory Meets Nanomaterials, Biotechnology and Health)
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21 pages, 3769 KiB  
Article
Probing Protein Folding with Sequence-Reversed α-Helical Bundles
by Aikaterini Kefala, Maria Amprazi, Efstratios Mylonas, Dina Kotsifaki, Mary Providaki, Charalambos Pozidis, Melina Fotiadou and Michael Kokkinidis
Int. J. Mol. Sci. 2021, 22(4), 1955; https://doi.org/10.3390/ijms22041955 - 16 Feb 2021
Cited by 8 | Viewed by 3182
Abstract
Recurrent protein folding motifs include various types of helical bundles formed by α-helices that supercoil around each other. While specific patterns of amino acid residues (heptad repeats) characterize the highly versatile folding motif of four-α-helical bundles, the significance of the polypeptide chain directionality [...] Read more.
Recurrent protein folding motifs include various types of helical bundles formed by α-helices that supercoil around each other. While specific patterns of amino acid residues (heptad repeats) characterize the highly versatile folding motif of four-α-helical bundles, the significance of the polypeptide chain directionality is not sufficiently understood, although it determines sequence patterns, helical dipoles, and other parameters for the folding and oligomerization processes of bundles. To investigate directionality aspects in sequence-structure relationships, we reversed the amino acid sequences of two well-characterized, highly regular four-α-helical bundle proteins and studied the folding, oligomerization, and structural properties of the retro-proteins, using Circular Dichroism Spectroscopy (CD), Size Exclusion Chromatography combined with Multi-Angle Laser Light Scattering (SEC-MALS), and Small Angle X-ray Scattering (SAXS). The comparison of the parent proteins with their retro-counterparts reveals that while the α-helical character of the parents is affected to varying degrees by sequence reversal, the folding states, oligomerization propensities, structural stabilities, and shapes of the new molecules strongly depend on the characteristics of the heptad repeat patterns. The highest similarities between parent and retro-proteins are associated with the presence of uninterrupted heptad patterns in helical bundles sequences. Full article
(This article belongs to the Special Issue Folding and Design of α-Helical Proteins and Peptides: Theory Meets Nanomaterials, Biotechnology and Health)
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Review

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25 pages, 8376 KiB  
Review
α-Helices in the Type III Secretion Effectors: A Prevalent Feature with Versatile Roles
by Anastasia D. Gazi, Michael Kokkinidis and Vasiliki E. Fadouloglou
Int. J. Mol. Sci. 2021, 22(11), 5412; https://doi.org/10.3390/ijms22115412 - 21 May 2021
Cited by 3 | Viewed by 2754
Abstract
Type III Secretion Systems (T3SSs) are multicomponent nanomachines located at the cell envelope of Gram-negative bacteria. Their main function is to transport bacterial proteins either extracellularly or directly into the eukaryotic host cell cytoplasm. Type III Secretion effectors (T3SEs), latest to be secreted [...] Read more.
Type III Secretion Systems (T3SSs) are multicomponent nanomachines located at the cell envelope of Gram-negative bacteria. Their main function is to transport bacterial proteins either extracellularly or directly into the eukaryotic host cell cytoplasm. Type III Secretion effectors (T3SEs), latest to be secreted T3S substrates, are destined to act at the eukaryotic host cell cytoplasm and occasionally at the nucleus, hijacking cellular processes through mimicking eukaryotic proteins. A broad range of functions is attributed to T3SEs, ranging from the manipulation of the host cell’s metabolism for the benefit of the bacterium to bypassing the host’s defense mechanisms. To perform this broad range of manipulations, T3SEs have evolved numerous novel folds that are compatible with some basic requirements: they should be able to easily unfold, pass through the narrow T3SS channel, and refold to an active form when on the other side. In this review, the various folds of T3SEs are presented with the emphasis placed on the functional and structural importance of α-helices and helical domains. Full article
(This article belongs to the Special Issue Folding and Design of α-Helical Proteins and Peptides: Theory Meets Nanomaterials, Biotechnology and Health)
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