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Molecular Insights into Macromolecules Structure, Function, and Regulation

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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 (30 December 2023) | Viewed by 28807

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Dr. Zhiwei Yang

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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,

Macromolecules are huge molecules with a diameter ranging from about 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 to implement reliable predictions: i) accurate modeling of the protein structure and “binding pocket”, ii) correct incorporation of the intrinsically dynamic behavior of proteins. Moreover, protein structure and function can be altered by mutations. 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 uncovering the ligand–protein / peptide–protein / protein–protein interaction modulations. Papers that explore all aspects are welcome, including the current efforts in theoretical developments.

Dr. Zhiwei Yang
Guest Editor

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Keywords

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

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 457 KiB

Open AccessEditorial

Molecular Insights into Macromolecules Structure, Function, and Regulation

by Zhiwei Yang and Jiasheng Zhao

Int. J. Mol. Sci. 2024, 25(10), 5296; https://doi.org/10.3390/ijms25105296 - 13 May 2024

Viewed by 971

Abstract

Macromolecules exhibit ordered structures and complex functions in an aqueous environment with strong thermodynamic fluctuations [...] Full article

(This article belongs to the Special Issue Molecular Insights into Macromolecules Structure, Function, and Regulation)

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Research

Jump to: Editorial, Review

14 pages, 2036 KiB

Open AccessArticle

Exploration of the Character Representation of DNA Chiral Conformations and Deformations via a Curved Surface Discrete Frenet Frame

by Ying Wang, He Wang, Shengli Zhang, Zhiwei Yang, Xuguang Shi and Lei Zhang

Int. J. Mol. Sci. 2024, 25(1), 4; https://doi.org/10.3390/ijms25010004 - 19 Dec 2023

Cited by 3 | Viewed by 1025

Abstract

While undergoing structural deformation, DNA experiences changes in the interactions between its internal base pairs, presenting challenges to conventional elastic methods. To address this, we propose the Discrete Critical State (DCS) model in this paper. This model combines surface discrete frame theory with gauge theory and Landau phase transition theory to investigate DNA’s structural deformation, phase transitions, and chirality. Notably, the DCS model considers both the internal interactions within DNA and formulates an overall equation using unified physical and geometric parameters. By employing the discrete frame, we derive the evolution of physical quantities along the helical axis of DNA, including geodesic curvature, geodesic torsion, and others. Our findings indicate that B-DNA has a significantly lower free energy density compared to Z-DNA, which is in agreement with experimental observations. This research reveals that the direction of base pairs is primarily governed by the geodesic curve within the helical plane, aligning closely with the orientation of the base pairs. Moreover, the geodesic curve has a profound influence on the arrangement of base pairs at the microscopic level and effectively regulates the configuration and geometry of DNA through macroscopic-level free energy considerations. Full article

(This article belongs to the Special Issue Molecular Insights into Macromolecules Structure, Function, and Regulation)

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13 pages, 3062 KiB

Open AccessArticle

Development of Apoptotic-Cell-Inspired Antibody–Drug Conjugate for Effective Immune Modulation

by Gyeongwoo Lee, Taishu Iwase, Shunsuke Matsumoto, Ahmed Nabil and Mitsuhiro Ebara

Int. J. Mol. Sci. 2023, 24(22), 16036; https://doi.org/10.3390/ijms242216036 - 7 Nov 2023

Cited by 2 | Viewed by 1996

Abstract

Background: Apoptotic cells’ phosphoserine (PS) groups have a significant immunosuppressive effect. They inhibit proinflammatory signals by interacting with various immune cells, including macrophages, dendritic cells, and CD4⁺ cells. Previously, we synthesized PS-group-immobilized polymers and verified their immunomodulatory effects. Despite its confirmed immunomodulatory potential, the PS group has not been considered as a payload for antibody–drug conjugates (ADCs) in a targeted anti-inflammatory approach. Aim: We conducted this research to introduce an apoptotic-cell-inspired antibody–drug conjugate for effective immunomodulation. Method: Poly(2-hydroxyethyl methacrylate-co-2-methacryloyloxyethyl phosphorylserine) (p(HEMA-co-MPS)) was synthesized as a payload using RAFT polymerization, and goat anti-mouse IgG was selected as a model antibody, which was conjugated with the synthesized p(HEMA-co-MPS) via 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-Hydroxysuccinimide (EDC/NHS) reaction. The antibody-binding affinity, anti-inflammatory potential, and cytotoxicity measurements were evaluated. Results: We successfully synthesized ADCs with a significant anti-inflammatory effect and optimized the antibody–polymer ratio to achieve the highest antibody-binding affinity. Conclusion: We successfully introduced p(HEMA-co-MPS) to IgG without decreasing the anti-inflammatory potential of the polymer while maintaining its targeting ability. We suggest that the antibody–polymer ratio be appropriately adjusted for effective therapy. In the future, this technology can be applied to therapeutic antibodies, such as Tocilizumab or Abatacept. Full article

(This article belongs to the Special Issue Molecular Insights into Macromolecules Structure, Function, and Regulation)

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17 pages, 2733 KiB

Open AccessArticle

Refolding Increases the Chaperone-like Activity of α_H-Crystallin and Reduces Its Hydrodynamic Diameter to That of α-Crystallin

by Konstantin O. Muranov, Nicolay B. Poliansky, Vera A. Borzova and Sergey Y. Kleimenov

Int. J. Mol. Sci. 2023, 24(17), 13473; https://doi.org/10.3390/ijms241713473 - 30 Aug 2023

Cited by 2 | Viewed by 1291

Abstract

α_H-Crystallin, a high molecular weight form of α-crystallin, is one of the major proteins in the lens nucleus. This high molecular weight aggregate (HMWA) plays an important role in the pathogenesis of cataracts. We have shown that the chaperone-like activity of HMWA is 40% of that of α-crystallin from the lens cortex. Refolding with urea significantly increased—up to 260%—the chaperone-like activity of α-crystallin and slightly reduced its hydrodynamic diameter (D_h). HMWA refolding resulted in an increase in chaperone-like activity up to 120% and a significant reduction of D_h of protein particles compared with that of α-crystallin. It was shown that the chaperone-like activity of HMWA, α-crystallin, and refolded α-crystallin but not refolded HMWA was strongly correlated with the denaturation enthalpy measured with differential scanning calorimetry (DSC). The DSC data demonstrated a significant increase in the native protein portion of refolded α-crystallin in comparison with authentic α-crystallin; however, the denaturation enthalpy of refolded HMWA was significantly decreased in comparison with authentic HMWA. The authors suggested that the increase in the chaperone-like activity of both α-crystallin and HMWA could be the result of the correction of misfolded proteins during renaturation and the rearrangement of protein supramolecular structures. Full article

(This article belongs to the Special Issue Molecular Insights into Macromolecules Structure, Function, and Regulation)

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18 pages, 4838 KiB

Open AccessArticle

Dissecting the Structural Dynamics of Authentic Cholesteryl Ester Transfer Protein for the Discovery of Potential Lead Compounds: A Theoretical Study

by Yizhen Zhao, Dongxiao Hao, Yifan Zhao, Shengli Zhang, Lei Zhang and Zhiwei Yang

Int. J. Mol. Sci. 2023, 24(15), 12252; https://doi.org/10.3390/ijms241512252 - 31 Jul 2023

Cited by 1 | Viewed by 1182

Abstract

Current structural and functional investigations of cholesteryl ester transfer protein (CETP) inhibitor design are nearly entirely based on a fully active mutation (CETP^Mutant) constructed for protein crystallization, limiting the study of the dynamic structural features of authentic CETP involved in lipid transport under physiological conditions. In this study, we conducted comprehensive molecular dynamics (MD) simulations of both authentic CETP (CETP^Authentic) and CETP^Mutant. Considering the structural differences between the N- and C-terminal domains of CETP^Authentic and CETP^Mutant, and their crucial roles in lipid transfer, we identified the two domains as binding pockets of the ligands for virtual screening to discover potential lead compounds targeting CETP. Our results revealed that CETP^Authentic displays greater flexibility and pronounced curvature compared to CETP^Mutant. Employing virtual screening and MD simulation strategies, we found that ZINC000006242926 has a higher binding affinity for the N- and C-termini, leading to reduced N- and C-opening sizes, disruption of the continuous tunnel, and increased curvature of CETP. In conclusion, CETP^Authentic facilitates the formation of a continuous tunnel in the “neck” region, while CETP^Mutant does not exhibit such characteristics. The ligand ZINC000006242926 screened for binding to the N- and C-termini induces structural changes in the CETP unfavorable to lipid transport. This study sheds new light on the relationship between the structural and functional mechanisms of CETP. Furthermore, it provides novel ideas for the precise regulation of CETP functions. Full article

(This article belongs to the Special Issue Molecular Insights into Macromolecules Structure, Function, and Regulation)

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20 pages, 8253 KiB

Open AccessArticle

Structural Modifications Introduced by NS2B Cofactor Binding to the NS3 Protease of the Kyasanur Forest Disease Virus

by Shivananda Kandagalla, Bhimanagoud Kumbar and Jurica Novak

Int. J. Mol. Sci. 2023, 24(13), 10907; https://doi.org/10.3390/ijms241310907 - 30 Jun 2023

Cited by 3 | Viewed by 1759

Abstract

Kyasanur Forest Disease virus (KFDV), a neglected human pathogenic virus, is a Flavivirus that causes severe hemorrhagic fever in humans. KFDV is transmitted to humans by the bite of the hard tick (Haemaphysalis spinigera), which acts as a reservoir of KFDV. The recent expansion of the endemic area of KFDV is of concern and requires the development of new preventive measures against KFDV. Currently, there is no antiviral therapy against KFDV, and the existing vaccine has limited efficacy. To develop a new antiviral therapy against KFDV, we focused on the nonstructural proteins NS2B and NS3 of KFDV, which are responsible for serine protease activity. Viral proteases have shown to be suitable therapeutic targets in the development of antiviral drugs against many diseases. However, success has been limited in flaviviruses, mainly because of the important features of the active site, which is flat and highly charged. In this context, the present study focuses on the dynamics of NS2B and NS3 to identify potential allosteric sites in the NS2B/NS3 protease of KDFV. To our knowledge, there are no reports on the dynamics of NS2B and NS3 in KFDV, and the crystal structure of the NS2B/NS3 protease of KFDV has not yet been solved. Overall, we created the structure of the NS2B/NS3 protease of KFDV using AlphaFold and performed molecular dynamics simulations with and without NS2B cofactor to investigate structural rearrangements due to cofactor binding and to identify alternative allosteric sites. The identified allosteric site is promising due to its geometric and physicochemical properties and druggability and can be used for new drug development. The applicability of the proposed allosteric binding sites was verified for the best-hit molecules from the virtual screening and MD simulations. Full article

(This article belongs to the Special Issue Molecular Insights into Macromolecules Structure, Function, and Regulation)

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15 pages, 7954 KiB

Open AccessArticle

Identification of Potential Lead Compounds Targeting Novel Druggable Cavity of SARS-CoV-2 Spike Trimer by Molecular Dynamics Simulations

by Yizhen Zhao, Yifan Zhao, Linke Xie, Qian Li, Yuze Zhang, Yongjian Zang, Xuhua Li, Lei Zhang and Zhiwei Yang

Int. J. Mol. Sci. 2023, 24(7), 6281; https://doi.org/10.3390/ijms24076281 - 27 Mar 2023

Cited by 6 | Viewed by 2056

Abstract

The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become an urgent public health problem. Spike (S) protein mediates the fusion between the virus and the host cell membranes, consequently emerging as an important target of drug design. The lack of comparisons of in situ full-length S homotrimer structures in different states hinders understanding the structures and revealing the function, thereby limiting the discovery and development of therapeutic agents. Here, the steady-state structures of the in situ full-length S trimer in closed and open states (S^closed and S^open) were modeled with the constraints of density maps, associated with the analysis of the dynamic structural differences. Subsequently, we identified various regions with structure and property differences as potential binding pockets for ligands that promote the formation of inactive trimeric protein complexes. By using virtual screening strategy and a newly defined druggable cavity, five ligands were screened with potential bioactivities. Then molecular dynamic (MD) simulations were performed on apo protein structures and ligand bound complexes to reveal the conformational changes upon ligand binding. Our simulation results revealed that sulforaphane (SFN), which has the best binding affinity, could inhibit the conformational changes of S homotrimer that would occur during the viral membrane fusion. Our results could aid in the understanding of the regulation mechanism of S trimer aggregation and the structure-activity relationship, facilitating the development of potential antiviral agents. Full article

(This article belongs to the Special Issue Molecular Insights into Macromolecules Structure, Function, and Regulation)

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20 pages, 3555 KiB

Open AccessArticle

Structural and Functional Characterization of a New Bacterial Dipeptidyl Peptidase III Involved in Fruiting Body Formation in Myxobacteria

by Si-Bo Chen, Han Zhang, Si Chen, Xian-Feng Ye, Zhou-Kun Li, Wei-Dong Liu, Zhong-Li Cui and Yan Huang

Int. J. Mol. Sci. 2023, 24(1), 631; https://doi.org/10.3390/ijms24010631 - 30 Dec 2022

Cited by 5 | Viewed by 1637

Abstract

Dipeptidyl peptidase III (DPP III) is a zinc-dependent enzyme that specifically hydrolyzes dipeptides from the N-terminal of different-length peptides, and it is involved in a number of physiological processes. Here, DPP III with an atypical pentapeptide zinc binding motif (HELMH) was identified from Corallococcus sp. EGB. It was shown that the activity of recombined CoDPP III was optimal at 50 °C and pH 7.0 with high thermostability up to 60 °C. Unique to CoDPP III, the crystal structure of the ligand-free enzyme was determined as a dimeric and closed form. The relatively small inter-domain cleft creates a narrower entrance to the substrate binding site and the unfavorable binding of the bulky naphthalene ring. The ectopic expression of CoDPP III in M. xanthus DK1622 resulted in a 12 h head start in fruiting body development compared with the wild type. Additionally, the A-signal prepared from the starving DK1622-CoDPP III rescued the developmental defect of the asgA mutant, and the fruiting bodies were more numerous and closely packed. Our data suggested that CoDPP III played a role in the fruiting body development of myxobacteria through the accumulation of peptides and amino acids to act as the A-signal. Full article

(This article belongs to the Special Issue Molecular Insights into Macromolecules Structure, Function, and Regulation)

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12 pages, 3671 KiB

Open AccessCommunication

Complete Models of p53 Better Inform the Impact of Hotspot Mutations

by Maria J. Solares and Deborah F. Kelly

Int. J. Mol. Sci. 2022, 23(23), 15267; https://doi.org/10.3390/ijms232315267 - 3 Dec 2022

Cited by 3 | Viewed by 11207

Abstract

Mutations in tumor suppressor genes often lead to cancerous phenotypes. Current treatments leverage signaling pathways that are often compromised by disease-derived deficiencies in tumor suppressors. P53 falls into this category as genetic mutations lead to physical changes in the protein that impact multiple cellular pathways. Here, we show the first complete structural models of mutated p53 to reveal how hotspot mutations physically deviate from the wild-type protein. We employed a recently determined structure for the p53 monomer to map seven frequent clinical mutations using computational modeling approaches. Results showed that missense mutations often changed the conformational structure of p53 in the DNA-binding site along with its electrostatic surface charges. We posit these changes may amplify the toxic effects of these hotspot mutations by destabilizing an important zinc ion coordination region in p53 to impede proper DNA interactions. These results highlight the imperative need for new studies on patient-derived proteins that may assist in redesigning structure-informed targeted therapies. Full article

(This article belongs to the Special Issue Molecular Insights into Macromolecules Structure, Function, and Regulation)

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13 pages, 12090 KiB

Open AccessArticle

Insights into Allosteric Mechanisms of the Lung-Enriched p53 Mutants V157F and R158L

by Jiangtao Lei, Xuanyao Li, Mengqiang Cai, Tianjing Guo, Dongdong Lin, Xiaohua Deng and Yin Li

Int. J. Mol. Sci. 2022, 23(17), 10100; https://doi.org/10.3390/ijms231710100 - 3 Sep 2022

Cited by 3 | Viewed by 2347

Abstract

Lung cancer is a leading fatal malignancy in humans. p53 mutants exhibit not only loss of tumor suppressor capability but also oncogenic gain-of-function, contributing to lung cancer initiation, progression and therapeutic resistance. Research shows that p53 mutants V157F and R158L occur with high frequency in lung squamous cell carcinomas. Revealing their conformational dynamics is critical for developing novel lung therapies. Here, we used all-atom molecular dynamics (MD) simulations to investigate the effect of V157F and R158L substitutions on the structural properties of the p53 core domain (p53C). Compared to wild-type (WT) p53C, both V157F and R158L mutants display slightly lesser β-sheet structure, larger radius of gyration, larger volume and larger exposed surface area, showing aggregation-prone structural characteristics. The aggregation-prone fragments (residues 249–267 and 268–282) of two mutants are more exposed to water solution than that of WT p53C. V157F and R158L mutation sites can affect the conformation switch of loop 1 through long-range associations. Simulations also reveal that the local structure and conformation around the V157F and R158L mutation sites are in a dynamic equilibrium between the misfolded and properly folded conformations. These results provide molecular mechanistic insights into allosteric mechanisms of the lung-enriched p53 mutants. Full article

(This article belongs to the Special Issue Molecular Insights into Macromolecules Structure, Function, and Regulation)

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Review

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24 pages, 943 KiB

Open AccessReview

Transcription Factors and Their Regulatory Roles in the Male Gametophyte Development of Flowering Plants

by Zhihao Qian, Dexi Shi, Hongxia Zhang, Zhenzhen Li, Li Huang, Xiufeng Yan and Sue Lin

Int. J. Mol. Sci. 2024, 25(1), 566; https://doi.org/10.3390/ijms25010566 - 1 Jan 2024

Cited by 2 | Viewed by 1953

Abstract

Male gametophyte development in plants relies on the functions of numerous genes, whose expression is regulated by transcription factors (TFs), non-coding RNAs, hormones, and diverse environmental stresses. Several excellent reviews are available that address the genes and enzymes associated with male gametophyte development, especially pollen wall formation. Growing evidence from genetic studies, transcriptome analysis, and gene-by-gene studies suggests that TFs coordinate with epigenetic machinery to regulate the expression of these genes and enzymes for the sequential male gametophyte development. However, very little summarization has been performed to comprehensively review their intricate regulatory roles and discuss their downstream targets and upstream regulators in this unique process. In the present review, we highlight the research progress on the regulatory roles of TF families in the male gametophyte development of flowering plants. The transcriptional regulation, epigenetic control, and other regulators of TFs involved in male gametophyte development are also addressed. Full article

(This article belongs to the Special Issue Molecular Insights into Macromolecules Structure, Function, and Regulation)

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