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Advanced Research on Protein Structure and Protein Dynamics
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Advanced Research on Protein Structure and Protein Dynamics

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

Deadline for manuscript submissions: 20 August 2025 | Viewed by 7995

Special Issue Editor

Dr. Robert T. Youker

E-Mail Website
Guest Editor
Department of Biology, Western Carolina University, Cullowhee, NC, USA
Interests: cystic fibrosis; protein folding and quality control; protein trafficking; chaperones
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Proteins are critical “workhorses” in the cells of all living organisms and are essential for a variety of processes, such as signal transduction, cell division, and metabolic pathways. Biophysical and biochemical studies have revealed that proteins are not static entities but are subject to dramatic molecular movements that span from femtosecond vibrations of atoms to slow motions of domains that can last for micro-to-milliseconds. The field of protein dynamics endeavors to study these complex molecular motions. Advances in biophysical and computational techniques are providing new insights into these protein structural changes. For example, the use of cryogenic-electron microscopy (cryo-EM) has led to greater insight into the molecular motions of G-protein coupled receptors upon ligand binding and activation. Combining structural studies with molecular dynamic simulations has been instrumental in investigating the protein folding problem and led to new hypotheses and avenues of research. The latest generation of computing hardware combined with artificial intelligence (AI) promises to advance the field of protein dynamics.

Researchers that utilize biophysical (e.g., cryo-EM, X-ray crystallography, NMR), biochemical (e.g., Fluorescence Fluctuation Techniques), or computational techniques (e.g., molecular dynamic simulations) applied to any domain of cell and molecular biology are welcome to submit their work for consideration. This Special Issue aims to showcase original research articles, reviews, mini-reviews, and commentaries describing the current knowledge of protein dynamics and the protein structural changes that contribute to these molecular movements.

Dr. Robert T. Youker
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.

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Keywords

  • allostery
  • receptor
  • kinase
  • protein folding
  • simulations
  • X-ray crystallography
  • NMR
  • super-resolution imaging
  • fluorescence fluctuation techniques
  • thermodynamic
  • enzyme
  • catalysis
  • artificial intelligence

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Published Papers (5 papers)

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Research

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31 pages, 17364 KiB  
Article
Structural Insights into the Dynamics of Water in SOD1 Catalysis and Drug Interactions
by Ilkin Yapici, Arda Gorkem Tokur, Belgin Sever, Halilibrahim Ciftci, Ayse Nazli Basak and Hasan DeMirci
Int. J. Mol. Sci. 2025, 26(9), 4228; https://doi.org/10.3390/ijms26094228 - 29 Apr 2025
Viewed by 272
Abstract
Superoxide dismutase 1 (SOD1) is a crucial enzyme that protects cells from oxidative damage by converting superoxide radicals into H2O2 and O2. This detoxification process, essential for cellular homeostasis, relies on a precisely orchestrated catalytic mechanism involving the [...] Read more.
Superoxide dismutase 1 (SOD1) is a crucial enzyme that protects cells from oxidative damage by converting superoxide radicals into H2O2 and O2. This detoxification process, essential for cellular homeostasis, relies on a precisely orchestrated catalytic mechanism involving the copper cation, while the zinc cation contributes to the structural integrity of the enzyme. This study presents the 2.3 Å crystal structure of human SOD1 (PDB ID: 9IYK), revealing an assembly of six homodimers and twelve distinct active sites. The water molecules form a complex hydrogen-bonding network that drives proton transfer and sustains active site dynamics. Our structure also uncovers subtle conformational changes that highlight the intrinsic flexibility of SOD1, which is essential for its function. Additionally, we observe how these dynamic structural features may be linked to pathological mutations associated with amyotrophic lateral sclerosis (ALS). By advancing our understanding of hSOD1’s mechanistic intricacies and the influence of water coordination, this study offers valuable insights for developing therapeutic strategies targeting ALS. Our structure’s unique conformations and active site interactions illuminate new facets of hSOD1 function, underscoring the critical role of structural dynamics in enzyme catalysis. Moreover, we conducted a molecular docking analysis using SOD1 for potential radical scavengers and Abelson non-receptor tyrosine kinase (c-Abl, Abl1) inhibitors targeting misfolded SOD1 aggregation along with oxidative stress and apoptosis, respectively. The results showed that CHEMBL1075867, a free radical scavenger derivative, showed the most promising docking results and interactions at the binding site of hSOD1, highlighting its promising role for further studies against SOD1-mediated ALS. Full article
(This article belongs to the Special Issue Advanced Research on Protein Structure and Protein Dynamics)
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25 pages, 3049 KiB  
Article
HCM-Associated MuRF1 Variants Compromise Ubiquitylation and Are Predicted to Alter Protein Structure
by Jitpisute Chunthorng-Orn, Maya Noureddine, Peter W. J. Dawson, Samuel O. Lord, Jimi Ng, Luke Boyton, Katja Gehmlich, Fiyaz Mohammed and Yu-Chiang Lai
Int. J. Mol. Sci. 2025, 26(8), 3921; https://doi.org/10.3390/ijms26083921 - 21 Apr 2025
Viewed by 613
Abstract
MuRF1 [muscle RING (Really Interesting New Gene)-finger protein-1] is an ubiquitin-protein ligase (E3), which encode by TRIM63 (tripartite motif containing 63) gene, playing a crucial role in regulating cardiac muscle size and function through ubiquitylation. Among hypertrophic cardiomyopathy (HCM) patients, 24 [...] Read more.
MuRF1 [muscle RING (Really Interesting New Gene)-finger protein-1] is an ubiquitin-protein ligase (E3), which encode by TRIM63 (tripartite motif containing 63) gene, playing a crucial role in regulating cardiac muscle size and function through ubiquitylation. Among hypertrophic cardiomyopathy (HCM) patients, 24 TRIM63 variants have been identified, with 1 additional variant linked to restrictive cardiomyopathy. However, only three variants have been previously investigated for their functional effects. The structural impacts of the 25 variants remain unexplored. This study investigated the effects of 25 MuRF1 variants on ubiquitylation activity using in vitro ubiquitylation assays and structural predictions using computational approaches. The variants were generated using site-directed PCR (Polymerase Chain Reaction) mutagenesis and subsequently purified with amylose affinity chromatography. In vitro ubiquitylation assays demonstrated that all 25 variants compromised the ability of MuRF1 to monoubiquitylate a titin fragment (A168-A170), while 17 variants significantly impaired or completely abolished auto-monoubiquitylation. Structural modelling predicted that 10 MuRF1 variants disrupted zinc binding or key stabilising interactions, compromising structural integrity. In contrast, three variants were predicted to enhance the structural stability of MuRF1, while six others were predicted to have no discernible impact on the structure. This study underscores the importance of functional assays and structural predictions in evaluating MuRF1 variant pathogenicity and provides novel insights into mechanisms by which these variants contribute to HCM and related cardiomyopathies. Full article
(This article belongs to the Special Issue Advanced Research on Protein Structure and Protein Dynamics)
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13 pages, 3665 KiB  
Article
Molecular Structure of the mRNA Export Factor Gle1 from Debaryomyces hansenii
by Min Jeong Jang, Soo Jin Lee and Jeong Ho Chang
Int. J. Mol. Sci. 2025, 26(4), 1661; https://doi.org/10.3390/ijms26041661 - 15 Feb 2025
Viewed by 453
Abstract
Gle1 functions as a regulator of Dbp5, a DEAD-box-containing RNA helicase that is a component of the nuclear pore complex. In association with Gle1 and inositol hexakisphosphate (IP6), ADP-bound Dbp5 facilitates the release of RNA. The RNA-bound Dbp5 undergoes ATP hydrolysis and is [...] Read more.
Gle1 functions as a regulator of Dbp5, a DEAD-box-containing RNA helicase that is a component of the nuclear pore complex. In association with Gle1 and inositol hexakisphosphate (IP6), ADP-bound Dbp5 facilitates the release of RNA. The RNA-bound Dbp5 undergoes ATP hydrolysis and is activated by Gle1 in the presence of IP6. The formation of a ternary complex involving Dbp5, Gle1, and the nucleoporin Nup159 promotes ADP secretion and prevents RNA recombination. To date, several complex structures of Gle1 with its binding partners have been described; however, the structure of unbound Gle1 remains elusive. To investigate the structural features associated with complex formation, the crystal structure of N-terminally truncated Gle1 from Debaryomyces hansenii (DhGle1ΔN) was determined at a resolution of 1.5 Å. The DhGle1ΔN protein comprises 13 α-helices. Structural comparisons with homologs, all of which have been characterized in various complexes, revealed no significant conformational changes. However, several distinct secondary structural elements were identified in α1, α3, α4, and α8. This study may provide valuable insights into the architecture of yeast Gle1 proteins and their interactions with Dbp5, which is crucial for understanding the regulation of mRNA export. Full article
(This article belongs to the Special Issue Advanced Research on Protein Structure and Protein Dynamics)
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14 pages, 1904 KiB  
Article
A Machine Learning Approach to Identify Key Residues Involved in Protein–Protein Interactions Exemplified with SARS-CoV-2 Variants
by Léopold Quitté, Mickael Leclercq, Julien Prunier, Marie-Pier Scott-Boyer, Gautier Moroy and Arnaud Droit
Int. J. Mol. Sci. 2024, 25(12), 6535; https://doi.org/10.3390/ijms25126535 - 13 Jun 2024
Cited by 2 | Viewed by 1203
Abstract
Human infection with the coronavirus disease 2019 (COVID-19) is mediated by the binding of the spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to the human angiotensin-converting enzyme 2 (ACE2). The frequent mutations in the receptor-binding domain (RBD) of the [...] Read more.
Human infection with the coronavirus disease 2019 (COVID-19) is mediated by the binding of the spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to the human angiotensin-converting enzyme 2 (ACE2). The frequent mutations in the receptor-binding domain (RBD) of the spike protein induced the emergence of variants with increased contagion and can hinder vaccine efficiency. Hence, it is crucial to better understand the binding mechanisms of variant RBDs to human ACE2 and develop efficient methods to characterize this interaction. In this work, we present an approach that uses machine learning to analyze the molecular dynamics simulations of RBD variant trajectories bound to ACE2. Along with the binding free energy calculation, this method was used to characterize the major differences in ACE2-binding capacity of three SARS-CoV-2 RBD variants—namely the original Wuhan strain, Omicron BA.1, and the more recent Omicron BA.5 sublineages. Our analyses assessed the differences in binding free energy and shed light on how it affects the infectious rates of different variants. Furthermore, this approach successfully characterized key binding interactions and could be deployed as an efficient tool to predict different binding inhibitors to pave the way for new preventive and therapeutic strategies. Full article
(This article belongs to the Special Issue Advanced Research on Protein Structure and Protein Dynamics)
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Review

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29 pages, 3830 KiB  
Review
Utilizing Molecular Dynamics Simulations, Machine Learning, Cryo-EM, and NMR Spectroscopy to Predict and Validate Protein Dynamics
by Ahrum Son, Woojin Kim, Jongham Park, Wonseok Lee, Yerim Lee, Seongyun Choi and Hyunsoo Kim
Int. J. Mol. Sci. 2024, 25(17), 9725; https://doi.org/10.3390/ijms25179725 - 8 Sep 2024
Cited by 4 | Viewed by 4304
Abstract
Protein dynamics play a crucial role in biological function, encompassing motions ranging from atomic vibrations to large-scale conformational changes. Recent advancements in experimental techniques, computational methods, and artificial intelligence have revolutionized our understanding of protein dynamics. Nuclear magnetic resonance spectroscopy provides atomic-resolution insights, [...] Read more.
Protein dynamics play a crucial role in biological function, encompassing motions ranging from atomic vibrations to large-scale conformational changes. Recent advancements in experimental techniques, computational methods, and artificial intelligence have revolutionized our understanding of protein dynamics. Nuclear magnetic resonance spectroscopy provides atomic-resolution insights, while molecular dynamics simulations offer detailed trajectories of protein motions. Computational methods applied to X-ray crystallography and cryo-electron microscopy (cryo-EM) have enabled the exploration of protein dynamics, capturing conformational ensembles that were previously unattainable. The integration of machine learning, exemplified by AlphaFold2, has accelerated structure prediction and dynamics analysis. These approaches have revealed the importance of protein dynamics in allosteric regulation, enzyme catalysis, and intrinsically disordered proteins. The shift towards ensemble representations of protein structures and the application of single-molecule techniques have further enhanced our ability to capture the dynamic nature of proteins. Understanding protein dynamics is essential for elucidating biological mechanisms, designing drugs, and developing novel biocatalysts, marking a significant paradigm shift in structural biology and drug discovery. Full article
(This article belongs to the Special Issue Advanced Research on Protein Structure and Protein Dynamics)
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