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Advances in Protein Folding and Misfolding, and Relations to Functions

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

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 14312

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Special Issue Editor

Dr. Takeshi Kikuchi

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Guest Editor

College of Life Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu 525-8577, Shiga, Japan
Interests: computational chemistry; biophysics; bioinformatics; protein structure
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The protein folding has been tackled by many researchers in couple of decades, but there are still unsolved issues in this phenomenon. The folding processes of several proteins have been analyzed by various experimental, theoretical and computational techniques. Many proteins fold into their native 3D structures according to their amino acid sequence information. It is still an interesting problem to decode the information of the 3D structure formation in the amino acid sequence of a protein. How the folding mechanism of a protein changes during its evolution is also an interesting problem. That is, there are several interesting and significant problems in this field.

Such researches will also serve to clarify the various properties of intrinsically disordered proteins and protein misfolding, and may lead to develop a therapy of a disease caused by misfolding of a protein. These investigations will also clarify the origins of the functions of proteins.

Thus, we are planning this Special Issue for the aim of comprehensive understanding of protein folding and misfolding in the various aspects, that is, experiment, theory, computation evolution, medical issues and so on. We are also interesting to understand the relationships of folding to functions of various proteins. We are waiting your contribution.

Dr. Takeshi Kikuchi
Guest Editor

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Keywords

Protein 3D structure formation
Intrinsically disordered protein
Evolution
Experimental techniques
Bioinformatics
Misfolding disease

Published Papers (4 papers)

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Research

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13 pages, 5097 KiB

Open AccessArticle

Prediction of Monomeric and Dimeric Structures of CYP102A1 Using AlphaFold2 and AlphaFold Multimer and Assessment of Point Mutation Effect on the Efficiency of Intra- and Interprotein Electron Transfer

by Yuri D. Ivanov, Amir Taldaev, Andrey V. Lisitsa, Elena A. Ponomarenko and Alexander I. Archakov

Molecules 2022, 27(4), 1386; https://doi.org/10.3390/molecules27041386 - 18 Feb 2022

Cited by 16 | Viewed by 4279

Abstract

The three-dimensional structure of monomers and homodimers of CYP102A1/WT (wild-type) proteins and their A83F and A83I mutant forms was predicted using the AlphaFold2 (AF2) and AlphaFold Multimer (AFMultimer) programs, which were compared with the rate constants of hydroxylation reactions of these enzyme forms to determine the efficiency of intra- and interprotein electron transport in the CYP102A1 hydroxylase system. The electron transfer rate constants (k_et), which determine the rate of indole hydroxylation by the CYP102A1 system, were calculated based on the distances (R) between donor-acceptor prosthetic groups (PG) FAD→FMN→HEME of these proteins using factor β, which describes an exponential decay from R the speed of electron transport (ET) according to the tunnelling mechanism. It was shown that the structure of monomers in the homodimer, calculated using the AlpfaFold Multimer program, is in good agreement with the experimental structures of globular domains (HEME-, FMN-, and FAD-domains) in CYP102A1/WT obtained by X-ray structural analysis, and the structure of isolated monomers predicted in AF2 does not coincide with the structure of monomers in the homodimer, although a high level of similarity in individual domains remains. The structures of monomers and homodimers of A83F and A83I mutants were also calculated, and their structures were compared with the wild-type protein. Significant differences in the structure of all isolated monomers with respect to the structures of monomers in homodimers were also found for them, and at the same time, insignificant differences were revealed for all homodimers. Comparative analysis for CYP102A1/WT between the calculated intra- and interprotein distances FAD→FMN→HEME and the rate constants of hydroxylation in these proteins showed that the distance between prosthetic groups both in the monomer and in the dimer allows the implementation of electron transfer between PGs, which is consistent with experimental literature data about k_cat. For the mutant form of monomer A83I, an increase in the distance between PGs was obtained, which can restrict electron transportation compared to WT; however, for the dimer of this protein, a decrease in the distance between PGs was observed compared to the WT form, which can lead to an increase in the electron transfer rate constant and, accordingly, k_cat. For the monomer and homodimer of the A83F mutant, the calculations showed an increase in the distance between the PGs compared to the WT form, which should have led to a decrease in the electron transfer rate, but at the same time, for the homodimer, the approach of the aromatic group F262 with heme can speed up transportation for this form and, accordingly, the rate of hydroxylation. Full article

(This article belongs to the Special Issue Advances in Protein Folding and Misfolding, and Relations to Functions)

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19 pages, 40280 KiB

Open AccessArticle

Structural Refolding and Thermal Stability of Myoglobin in the Presence of Mixture of Crowders: Importance of Various Interactions for Protein Stabilization in Crowded Conditions

by Zahoor Ahmad Parray, Faizan Ahmad, Md. Imtaiyaz Hassan, Anwar Ahmed, Fahad N. Almajhdi, Ajamaluddin Malik, Tajamul Hussain and Asimul Islam

Molecules 2021, 26(9), 2807; https://doi.org/10.3390/molecules26092807 - 10 May 2021

Cited by 13 | Viewed by 2774

Abstract

The intracellular environment is overcrowded with a range of molecules (small and large), all of which influence protein conformation. As a result, understanding how proteins fold and stay functional in such crowded conditions is essential. Several in vitro experiments have looked into the effects of macromolecular crowding on different proteins. However, there are hardly any reports regarding small molecular crowders used alone and in mixtures to observe their effects on the structure and stability of the proteins, which mimics of the cellular conditions. Here we investigate the effect of different mixtures of crowders, ethylene glycol (EG) and its polymer polyethylene glycol (PEG 400 Da) on the structural and thermal stability of myoglobin (Mb). Our results show that monomer (EG) has no significant effect on the structure of Mb, while the polymer disrupts its structure and decreases its stability. Conversely, the additive effect of crowders showed structural refolding of the protein to some extent. Moreover, the calorimetric binding studies of the protein showed very weak interactions with the mixture of crowders. Usually, we can assume that soft interactions induce structural perturbations while exclusion volume effects stabilize the protein structure; therefore, we hypothesize that under in vivo crowded conditions, both phenomena occur and maintain the stability and function of proteins. Full article

(This article belongs to the Special Issue Advances in Protein Folding and Misfolding, and Relations to Functions)

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Review

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22 pages, 7449 KiB

Open AccessReview

Decoding an Amino Acid Sequence to Extract Information on Protein Folding

by Takeshi Kikuchi

Molecules 2022, 27(9), 3020; https://doi.org/10.3390/molecules27093020 - 07 May 2022

Cited by 1 | Viewed by 1819

Abstract

Protein folding is a complicated phenomenon including various time scales (μs to several s), and various structural indices are required to analyze it. The methodologies used to study this phenomenon also have a wide variety and employ various experimental and computational techniques. Thus, a simple speculation does not serve to understand the folding mechanism of a protein. In the present review, we discuss the recent studies conducted by the author and their colleagues to decode amino acid sequences to obtain information on protein folding. We investigate globin-like proteins, ferredoxin-like fold proteins, IgG-like beta-sandwich fold proteins, lysozyme-like fold proteins and β-trefoil-like fold proteins. Our techniques are based on statistics relating to the inter-residue average distance, and our studies performed so far indicate that the information obtained from these analyses includes data on the protein folding mechanism. The relationships between our results and the actual protein folding phenomena are also discussed. Full article

(This article belongs to the Special Issue Advances in Protein Folding and Misfolding, and Relations to Functions)

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11 pages, 5945 KiB

Open AccessReview

Significance of Oligomeric and Fibrillar Species in Amyloidosis: Insights into Pathophysiology and Treatment

by Haruki Koike, Yohei Iguchi, Kentaro Sahashi and Masahisa Katsuno

Molecules 2021, 26(16), 5091; https://doi.org/10.3390/molecules26165091 - 22 Aug 2021

Cited by 24 | Viewed by 4411

Abstract

Amyloidosis is a term referring to a group of various protein-misfolding diseases wherein normally soluble proteins form aggregates as insoluble amyloid fibrils. How, or whether, amyloid fibrils contribute to tissue damage in amyloidosis has been the topic of debate. In vitro studies have demonstrated the appearance of small globular oligomeric species during the incubation of amyloid beta peptide (Aβ). Nerve biopsy specimens from patients with systemic amyloidosis have suggested that globular structures similar to Aβ oligomers were generated from amorphous electron-dense materials and later developed into mature amyloid fibrils. Schwann cells adjacent to amyloid fibrils become atrophic and degenerative, suggesting that the direct tissue damage induced by amyloid fibrils plays an important role in systemic amyloidosis. In contrast, there is increasing evidence that oligomers, rather than amyloid fibrils, are responsible for cell death in neurodegenerative diseases, particularly Alzheimer’s disease. Disease-modifying therapies based on the pathophysiology of amyloidosis have now become available. Aducanumab, a human monoclonal antibody against the aggregated form of Aβ, was recently approved for Alzheimer’s disease, and other monoclonal antibodies, including gantenerumab, solanezumab, and lecanemab, could also be up for approval. As many other agents for amyloidosis will be developed in the future, studies to develop sensitive clinical scales for identifying improvement and markers that can act as surrogates for clinical scales should be conducted. Full article

(This article belongs to the Special Issue Advances in Protein Folding and Misfolding, and Relations to Functions)

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