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Molecular Insights into Macromolecules Structure, Function, and Regulation: 2nd Edition
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Molecular Insights into Macromolecules Structure, Function, and Regulation: 2nd Edition

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 (20 July 2025) | Viewed by 9771

Special Issue Editor

Dr. Zhiwei Yang

E-Mail Website
Guest Editor
School of Physics, Xi'an Jiaotong University, Xi'an 710049, China
Interests: dynamic structure; functional mechanism and artificial regulation of biomacromolecules
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our Special Issue titled “Molecular Insights into Macromolecules Structure, Function, and Regulation”.

Macromolecules are large molecules, with a diameter ranging from approximately 10 to 1000 nm. Proteins are common macromolecules in living organisms. Protein structures determine function, and the regulation of this structure often affects its function. In this Special Issue, we will focus on the structure, function and regulation of biomolecular proteins.

Nowadays, protein structure prediction/modeling has been routinely applied in drug discovery to increase its effectiveness. It provides essential contributions in successful predictions (e.g., antivirals for COVID-19), leading a battle against the pandemic and understanding the functional complexity of living systems. However, there are two main issues to be solved in order to implement reliable predictions: (i) accurate modeling of the protein structure and “binding pocket”; and (ii) correct incorporation of the intrinsically dynamic behavior of proteins. Moreover, protein structure and function can be altered by mutations, hence understanding the effects of mutations on protein structure and function is important for the prevention of related diseases and the development of therapeutic drugs. A variety of algorithms and strategies have been developed for the ever-improving estimation of structural modeling and drug discovery, accounting for conformational dynamics, including molecular simulation, deep learning, NMR, cryo-electron microscopy and single-molecule fluorescence techniques.

Accordingly, the aim of this Special Issue is to collect a series of state-of-the-art examples of the recent advances in this rapidly changing field, and uncover the ligand–protein/peptide–protein/protein–protein interaction modulations. Papers that explore all aspects are welcome, including current efforts in theoretical developments.

Dr. Zhiwei Yang
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 250 words) can be sent to the Editorial Office for assessment.

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

  • conformational dynamics
  • structural modeling
  • docking
  • molecular recognition
  • regulation mechanism
  • rational design
  • molecular dynamic simulation

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Published Papers (4 papers)

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Research

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23 pages, 6122 KB  
Article
Structural Basis for TGF-β Mimetic Peptide-Induced Signaling Activation Through Molecular Dynamics Simulations
by Chun Chen, Jingsong Ai, Junhui Huang, Xiaobin Li, Yiting Wang, Mingjie Tong, Xinshan Xie, Qiuling Xie and Sheng Xiong
Int. J. Mol. Sci. 2026, 27(1), 22; https://doi.org/10.3390/ijms27010022 - 19 Dec 2025
Viewed by 278
Abstract
Transforming growth factor-β (TGF-β) mimetic peptides offer significant therapeutic potential due to their superior pharmacological properties over the native cytokine. Our previous work identified two such peptides, TB1 and TB2, which bind to the type II TGF-β receptor (TβRII) yet elicit distinct cellular [...] Read more.
Transforming growth factor-β (TGF-β) mimetic peptides offer significant therapeutic potential due to their superior pharmacological properties over the native cytokine. Our previous work identified two such peptides, TB1 and TB2, which bind to the type II TGF-β receptor (TβRII) yet elicit distinct cellular responses. To uncover the mechanistic basis for the functional divergence, we employed integrated molecular dynamics (MD) simulations with the AlphaFold3-predicted structures. Our analytical results indicated that TB2 stabilizes a dynamic complex with TβRII and is predicted to facilitate type I receptor (TβRI) engagement possibly involving a critical hydrogen bond between TB2-Gly11 and TβRI-Phe60. The resulting trimeric assembly (TB2–TβRII–TβRI) exhibits a higher relative binding affinity (−67.76 ± 7.70 kcal/mol) and structural stability. In contrast, the TB1–TβRII complex fails to productively engage TβRI. These computational results were experimentally validated. Western blot analysis confirmed that TB2, but not TB1, activates the canonical TGF-β/Smad pathway by enhancing the expression and phosphorylation of Smad3. This study will elucidate the dynamic structural basis for the activity of TGF-β mimetic peptides and suggest TB2 as a promising lead candidate for the rational design of tissue-regenerative therapeutics. Full article
(This article belongs to the Special Issue Molecular Insights into Macromolecules Structure, Function, and Regulation: 2nd Edition)
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17 pages, 5385 KB  
Article
Mechanistic Insight into the Enantioselective Degradation of Esterase QeH to (R)/(S)–Quizalofop–Ethyl with Molecular Dynamics Simulation Using a Residue-Specific Force Field
by Yu-Meng Zhu, Gui Yao, Song Shao, Xin-Yu Liu, Jun Xu, Chun Chen, Xing-Wang Zhang, Zhuo-Ran Huang, Cheng-Zhen Xu, Long Zhang and Xiao-Min Wu
Int. J. Mol. Sci. 2024, 25(18), 9964; https://doi.org/10.3390/ijms25189964 - 15 Sep 2024
Cited by 2 | Viewed by 2113
Abstract
The enantioselective mechanism of the esterase QeH against the two enantiomers of quizalofop–ethyl (QE) has been primitively studied using computational and experimental approaches. However, it is still unclear how the esterase QeH adjusts its conformation to adapt to substrate binding and promote enzym [...] Read more.
The enantioselective mechanism of the esterase QeH against the two enantiomers of quizalofop–ethyl (QE) has been primitively studied using computational and experimental approaches. However, it is still unclear how the esterase QeH adjusts its conformation to adapt to substrate binding and promote enzyme–substrate interactions in the catalytic kinetics. The equilibrium processes of enzyme–substrate interactions and catalytic dynamics were reproduced by performing independent molecular dynamics (MD) runs on the QeH-(R)/(S)-QE complexes with a newly developed residue-specific force field (RSFF2C). Our results indicated that the benzene ring of the (R)-QE structure can simultaneously form anion–π and cation–π interactions with the side-chain group of Glu328 and Arg384 in the binding cavity of the QeH-(R)-QE complex, resulting in (R)-QE being closer to its catalytic triplet system (Ser78-Lys81-Tyr189) with the distances measured for the hydroxyl oxygen atom of the catalytic Ser78 of QeH and the carbonyl carbon atom of (R)-QE of 7.39 Å, compared to the 8.87 Å for (S)-QE, whereas the (S)-QE structure can only form an anion–π interaction with the side chain of Glu328 in the QeH-(S)-QE complex, being less close to its catalytic site. The computational alanine scanning mutation (CAS) calculations further demonstrated that the π–π stacking interaction between the indole ring of Trp351 and the benzene ring of (R)/(S)-QE contributed a lot to the binding stability of the enzyme–substrate (QeH-(R)/(S)-QE). These results facilitate the understanding of their catalytic processes and provide new theoretical guidance for the directional design of other key enzymes for the initial degradation of aryloxyphenoxypropionate (AOPP) herbicides with higher catalytic efficiencies. Full article
(This article belongs to the Special Issue Molecular Insights into Macromolecules Structure, Function, and Regulation: 2nd Edition)
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13 pages, 6359 KB  
Article
The Inhibition Effect of Epigallocatechin-3-Gallate on the Co-Aggregation of Amyloid-β and Human Islet Amyloid Polypeptide Revealed by Replica Exchange Molecular Dynamics Simulations
by Xuhua Li, Yu Zhang, Zhiwei Yang, Shengli Zhang and Lei Zhang
Int. J. Mol. Sci. 2024, 25(3), 1636; https://doi.org/10.3390/ijms25031636 - 29 Jan 2024
Cited by 6 | Viewed by 3217
Abstract
Alzheimer’s disease and Type 2 diabetes are two epidemiologically linked diseases which are closely associated with the misfolding and aggregation of amyloid proteins amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP), respectively. The co-aggregation of the two amyloid proteins is regarded as the [...] Read more.
Alzheimer’s disease and Type 2 diabetes are two epidemiologically linked diseases which are closely associated with the misfolding and aggregation of amyloid proteins amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP), respectively. The co-aggregation of the two amyloid proteins is regarded as the fundamental molecular mechanism underlying their pathological association. The green tea extract epigallocatechin-3-gallate (EGCG) has been extensively demonstrated to inhibit the amyloid aggregation of Aβ and hIAPP proteins. However, its potential role in amyloid co-aggregation has not been thoroughly investigated. In this study, we employed the enhanced-sampling replica exchange molecular dynamics simulation (REMD) method to investigate the effect of EGCG on the co-aggregation of Aβ and hIAPP. We found that EGCG molecules substantially diminish the β-sheet structures within the amyloid core regions of Aβ and hIAPP in their co-aggregates. Through hydrogen-bond, π–π and cation–π interactions targeting polar and aromatic residues of Aβ and hIAPP, EGCG effectively attenuates both inter-chain and intra-chain interactions within the co-aggregates. All these findings indicated that EGCG can effectively inhibit the co-aggregation of Aβ and hIAPP. Our study expands the potential applications of EGCG as an anti-amyloidosis agent and provides therapeutic options for the pathological association of amyloid misfolding disorders. Full article
(This article belongs to the Special Issue Molecular Insights into Macromolecules Structure, Function, and Regulation: 2nd Edition)
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Review

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16 pages, 1749 KB  
Review
Biological Significance and Therapeutic Promise of Programmed Ribosomal Frameshifting
by Miora Bruna Marielle Ramamonjiharisoa and Sen Liu
Int. J. Mol. Sci. 2025, 26(3), 1294; https://doi.org/10.3390/ijms26031294 - 3 Feb 2025
Cited by 1 | Viewed by 3197
Abstract
Programmed Ribosomal Frameshifting (PRF) is a mechanism that alters the mRNA reading frame during translation, resulting in the production of out-of-frame proteins. PRF plays crucial roles in maintaining cellular homeostasis and contributes significantly to disease pathogenesis, particularly in viral infections. Notably, PRF can [...] Read more.
Programmed Ribosomal Frameshifting (PRF) is a mechanism that alters the mRNA reading frame during translation, resulting in the production of out-of-frame proteins. PRF plays crucial roles in maintaining cellular homeostasis and contributes significantly to disease pathogenesis, particularly in viral infections. Notably, PRF can induce immune responses in the SARS-CoV-2 mRNA vaccine, further extending its biological significance. These multiple aspects of PRF highlight its potential as a therapeutic target. Since PRF efficiency can be modulated by cellular factors, its expression or silencing is context-dependent. Therefore, a deeper understanding of PRF is essential for harnessing its therapeutic potential. This review explores PRF biological significance in disease and homeostasis. Such knowledge would serve as a foundation to advance therapeutic strategies targeting PRF modulation, especially in viral infections and vaccine development. Full article
(This article belongs to the Special Issue Molecular Insights into Macromolecules Structure, Function, and Regulation: 2nd Edition)
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