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Protein Structure Dynamics and Function

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

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 18630

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Prof. Dr. Shin-ichi Tate

E-Mail Website1 Website2
Guest Editor

1. Department of Mathematical and Life Sciences, School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8526, Japan
2. Research Center for the Mathematics on Chromatin Live Dynamics (RcMcD), Hiroshima University, 1-3-1, Kagamiyama, Higashi-Hiroshima 739-8526, Japan
Interests: protein structure; protein structural dynamics; intrinsically disordered protein; protein aggregation; nuclear magnetic resonance spectroscopy
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Dear Colleagues,

Protein structural dynamics is intimately related to protein functions. Structure biology demands high-resolution structures primarily coming from X-ray crystallography. However, the crystal structure does not always give a comprehensive understanding of the functional mechanism. This inability is often ascribed to a lack of insight into the time-dependent spatial rearrangement of the regulatory residues, domains, and subunits in proteins, which emphasizes the importance in exploring how structural dynamics engages in functional regulation in proteins. Progress in the experimental and theoretical approaches has improved our understanding of protein structural dynamics and has updated the protein structure and function relationships by adding the roles of structural dynamics. The technical advances have also expanded the research targets from folded proteins to intrinsically disordered proteins that travel much wider conformational spaces over the folded proteins. Intrinsically disordered proteins with liquid–liquid phase separation properties have become focused, which unveils the other remarkable roles of structural dynamics in regulating the phase transition of the protein solution.

The Special Issue “Protein Structure Dynamics and Function” is a continuation of the successful 2018 and 2019 issue “Protein Structural Dynamics.” This issue also aims to present contemporary research on protein structural dynamics, which may include original articles covering technical development, experimental reports on some particular proteins, and theoretical research, as well as review papers relating to the topic.

Prof. Dr. Shin-ichi Tate
Guest Editor

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Keywords

Protein strutural dynamics
Enzyme functions
Intrinsically disordered proteins
NMR
Single molecular FRET (fluorecense resonance energy transfer)
Molecular dynamics simulation
Coarse grained molecular dynamics simulation

Published Papers (7 papers)

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Research

17 pages, 5296 KiB

Open AccessArticle

Dynamic Coupling of Tyrosine 185 with the Bacteriorhodopsin Photocycle, as Revealed by Chemical Shifts, Assisted AF-QM/MM Calculations and Molecular Dynamic Simulations

by Sijin Chen, Xiaoyan Ding, Chao Sun, Anthony Watts, Xiao He and Xin Zhao

Int. J. Mol. Sci. 2021, 22(24), 13587; https://doi.org/10.3390/ijms222413587 - 18 Dec 2021

Cited by 1 | Viewed by 2334

Abstract

Aromatic residues are highly conserved in microbial photoreceptors and play crucial roles in the dynamic regulation of receptor functions. However, little is known about the dynamic mechanism of the functional role of those highly conserved aromatic residues during the receptor photocycle. Tyrosine 185 (Y185) is a highly conserved aromatic residue within the retinal binding pocket of bacteriorhodopsin (bR). In this study, we explored the molecular mechanism of the dynamic coupling of Y185 with the bR photocycle by automated fragmentation quantum mechanics/molecular mechanics (AF-QM/MM) calculations and molecular dynamic (MD) simulations based on chemical shifts obtained by 2D solid-state NMR correlation experiments. We observed that Y185 plays a significant role in regulating the retinal cis–trans thermal equilibrium, stabilizing the pentagonal H-bond network, participating in the orientation switch of Schiff Base (SB) nitrogen, and opening the F42 gate by interacting with the retinal and several key residues along the proton translocation channel. Our findings provide a detailed molecular mechanism of the dynamic couplings of Y185 and the bR photocycle from a structural perspective. The method used in this paper may be applied to the study of other microbial photoreceptors. Full article

(This article belongs to the Special Issue Protein Structure Dynamics and Function)

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19 pages, 3057 KiB

Open AccessArticle

Molecular Mechanism of the Anti-Inflammatory Action of Heparin

by Leandar Litov, Peicho Petkov, Miroslav Rangelov, Nevena Ilieva, Elena Lilkova, Nadezhda Todorova, Elena Krachmarova, Kristina Malinova, Anastas Gospodinov, Rossitsa Hristova, Ivan Ivanov and Genoveva Nacheva

Int. J. Mol. Sci. 2021, 22(19), 10730; https://doi.org/10.3390/ijms221910730 - 03 Oct 2021

Cited by 23 | Viewed by 3533

Abstract

Our objective is to reveal the molecular mechanism of the anti-inflammatory action of low-molecular-weight heparin (LMWH) based on its influence on the activity of two key cytokines, IFNγ and IL-6. The mechanism of heparin binding to IFNγ and IL-6 and the resulting inhibition of their activity were studied by means of extensive molecular-dynamics simulations. The effect of LMWH on IFNγ signalling inside stimulated WISH cells was investigated by measuring its antiproliferative activity and the translocation of phosphorylated STAT1 in the nucleus. We found that LMWH binds with high affinity to IFNγ and is able to fully inhibit the interaction with its cellular receptor. It also influences the biological activity of IL-6 by binding to either IL-6 or IL-6/IL-6Rα, thus preventing the formation of the IL-6/IL-6Rα/gp130 signalling complex. These findings shed light on the molecular mechanism of the anti-inflammatory action of LMWH and underpin its ability to influence favourably conditions characterised by overexpression of these two cytokines. Such conditions are not only associated with autoimmune diseases, but also with inflammatory processes, in particular with COVID-19. Our results put forward heparin as a promising means for the prevention and suppression of severe CRS and encourage further investigations on its applicability as an anti-inflammatory agent. Full article

(This article belongs to the Special Issue Protein Structure Dynamics and Function)

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21 pages, 2885 KiB

Open AccessArticle

Low-Frequency Harmonic Perturbations Drive Protein Conformational Changes

by Domenico Scaramozzino, Gianfranco Piana, Giuseppe Lacidogna and Alberto Carpinteri

Int. J. Mol. Sci. 2021, 22(19), 10501; https://doi.org/10.3390/ijms221910501 - 28 Sep 2021

Cited by 5 | Viewed by 1973

Abstract

Protein dynamics has been investigated since almost half a century, as it is believed to constitute the fundamental connection between structure and function. Elastic network models (ENMs) have been widely used to predict protein dynamics, flexibility and the biological mechanism, from which remarkable results have been found regarding the prediction of protein conformational changes. Starting from the knowledge of the reference structure only, these conformational changes have been usually predicted either by looking at the individual mode shapes of vibrations (i.e., by considering the free vibrations of the ENM) or by applying static perturbations to the protein network (i.e., by considering a linear response theory). In this paper, we put together the two previous approaches and evaluate the complete protein response under the application of dynamic perturbations. Harmonic forces with random directions are applied to the protein ENM, which are meant to simulate the single frequency-dependent components of the collisions of the surrounding particles, and the protein response is computed by solving the dynamic equations in the underdamped regime, where mass, viscous damping and elastic stiffness contributions are explicitly taken into account. The obtained motion is investigated both in the coordinate space and in the sub-space of principal components (PCs). The results show that the application of perturbations in the low-frequency range is able to drive the protein conformational change, leading to remarkably high values of direction similarity. Eventually, this suggests that protein conformational change might be triggered by external collisions and favored by the inherent low-frequency dynamics of the protein structure. Full article

(This article belongs to the Special Issue Protein Structure Dynamics and Function)

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10 pages, 1698 KiB

Open AccessArticle

Tau N-Terminal Inserts Regulate Tau Liquid-Liquid Phase Separation and Condensates Maturation in a Neuronal Cell Model

by Chengchen Wu, Junyi Zhao, Qiuping Wu, Qiulong Tan, Qiong Liu and Shifeng Xiao

Int. J. Mol. Sci. 2021, 22(18), 9728; https://doi.org/10.3390/ijms22189728 - 08 Sep 2021

Cited by 11 | Viewed by 2895

Abstract

The microtubule-associated protein tau can undergo liquid–liquid phase separation (LLPS) to form membraneless condensates in neurons, yet the underlying molecular mechanisms and functions of tau LLPS and tau droplets remain to be elucidated. The human brain contains mainly 6 tau isoforms with different numbers of microtubule-binding repeats (3R, 4R) and N-terminal inserts (0N, 1N, 2N). However, little is known about the role of N-terminal inserts. Here we observed the dynamics of three tau isoforms with different N-terminal inserts in live neuronal cell line HT22. We validated tau LLPS in cytoplasm and found that 2N-tau forms liquid-like, hollow-shell droplets. Tau condensates became smaller in 1N-tau comparing with 2N-tau, while no obvious tau accumulated dots were shown in 0N-tau. The absence of N-terminal inserts significantly affected condensate colocalization of tau and p62. The results reveal insights into the tau LLPS assembly mechanism and functional effects of N-terminal inserts in tau. Full article

(This article belongs to the Special Issue Protein Structure Dynamics and Function)

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12 pages, 2957 KiB

Open AccessArticle

Crystal Structure of the Epo1-Bem3 Complex for Bud Growth

by Jin Wang, Lei Li, Zhenhua Ming, Lijie Wu and Liming Yan

Int. J. Mol. Sci. 2021, 22(8), 3812; https://doi.org/10.3390/ijms22083812 - 07 Apr 2021

Viewed by 1776

Abstract

Tubules of the endoplasmic reticulum (ER) spread into the buds of yeast by an actin-based mechanism and, upon entry, become attached to the polarisome, a proteinaceous micro-compartment below the tip of the bud. The minimal tether between polarisome and cortical ER is formed by a protein complex consisting of Epo1, a member of the polarisome, Scs2, a membrane protein of the ER and Cdc42 guanosine triphosphatase-activating protein Bem3. Here, we report the crystal structure of a complex between Epo1 and Bem3. In addition, we characterize through the hydrogen/deuterium (H/D) exchange assay the interface between Scs2 and Epo1. Our findings provide a first structural insight into the molecular architecture of the link between cortical ER and the polarisome. Full article

(This article belongs to the Special Issue Protein Structure Dynamics and Function)

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7 pages, 268 KiB

Open AccessArticle

The Finite Size Effects and Two-State Paradigm of Protein Folding

by Artem Badasyan, Matjaz Valant, Jože Grdadolnik and Vladimir N. Uversky

Int. J. Mol. Sci. 2021, 22(4), 2184; https://doi.org/10.3390/ijms22042184 - 22 Feb 2021

Cited by 2 | Viewed by 1866

Abstract

The coil to globule transition of the polypeptide chain is the physical phenomenon behind the folding of globular proteins. Globular proteins with a single domain usually consist of about 30 to 100 amino acid residues, and this finite size extends the transition interval of the coil-globule phase transition. Based on the pedantic derivation of the two-state model, we introduce the number of amino acid residues of a polypeptide chain as a parameter in the expressions for two cooperativity measures and reveal their physical significance. We conclude that the

k_{2}

measure, defined as the ratio of van ’t Hoff and calorimetric enthalpy is related to the degeneracy of the denatured state and describes the number of cooperative units involved in the transition; additionally, it is found that the widely discussed

k_{2} = 1

is just the necessary condition to classify the protein as the two-state folder. We also find that

Ω_{c}

, a quantity not limited from above and growing with system size, is simply proportional to the square of the transition interval. This fact allows us to perform the classical size scaling analysis of the coil-globule phase transition. Moreover, these two measures are shown to describe different characteristics of protein folding. Full article

(This article belongs to the Special Issue Protein Structure Dynamics and Function)

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23 pages, 3855 KiB

Open AccessArticle

Interferon Beta Activity Is Modulated via Binding of Specific S100 Proteins

by Alexey S. Kazakov, Alexander D. Sofin, Nadezhda V. Avkhacheva, Alexander I. Denesyuk, Evgenia I. Deryusheva, Victoria A. Rastrygina, Andrey S. Sokolov, Maria E. Permyakova, Ekaterina A. Litus, Vladimir N. Uversky, Eugene A. Permyakov and Sergei E. Permyakov

Int. J. Mol. Sci. 2020, 21(24), 9473; https://doi.org/10.3390/ijms21249473 - 13 Dec 2020

Cited by 12 | Viewed by 2507

Abstract

Interferon-β (IFN-β) is a pleiotropic cytokine used for therapy of multiple sclerosis, which is also effective in suppression of viral and bacterial infections and cancer. Recently, we reported a highly specific interaction between IFN-β and S100P lowering IFN-β cytotoxicity to cancer cells (Int J Biol Macromol. 2020; 143: 633–639). S100P is a member of large family of multifunctional Ca²⁺-binding proteins with cytokine-like activities. To probe selectivity of IFN-β—S100 interaction with respect to S100 proteins, we used surface plasmon resonance spectroscopy, chemical crosslinking, and crystal violet assay. Among the thirteen S100 proteins studied S100A1, S100A4, and S100A6 proteins exhibit strictly Ca²⁺-dependent binding to IFN-β with equilibrium dissociation constants, K_d, of 0.04–1.5 µM for their Ca²⁺-bound homodimeric forms. Calcium depletion abolishes the S100—IFN-β interactions. Monomerization of S100A1/A4/A6 decreases K_d values down to 0.11–1.0 nM. Interferon-α is unable of binding to the S100 proteins studied. S100A1/A4 proteins inhibit IFN-β-induced suppression of MCF-7 cells viability. The revealed direct influence of specific S100 proteins on IFN-β activity uncovers a novel regulatory role of particular S100 proteins, and opens up novel approaches to enhancement of therapeutic efficacy of IFN-β. Full article

(This article belongs to the Special Issue Protein Structure Dynamics and Function)

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