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

Deadline for manuscript submissions: 31 May 2024 | Viewed by 4894

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Dr. Ivo Crnolatac

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Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia
Interests: biomolecular interactions; DNA/RNA; protein structure; protein function; drug discovery
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Special Issue Information

Dear Colleagues,

Biophysical chemistry is a truly interdisciplinary endeavour combining the principles of physics, biology, and chemistry to explore the processes in biological systems and their underlying physical and chemical properties. The focus is on understanding how biological molecules, such as proteins, nucleic acids, and lipids, interact with each other and with their environment at a molecular level. Thus, biomolecular interactions are a fundamental part of biophysical chemistry. We aim to publish important and exciting studies on protein–protein, protein–DNA, protein–ligand, and receptor–ligand interactions in this Special Issue. Furthermore, manuscripts on biomolecular structure and function, protein folding, and stability are welcome. Publications on innovations in biophysical techniques facilitating further progress in this prominent field of research would, likewise, be appreciated.

Dr. Ivo Crnolatac
Guest Editor

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Keywords

biophysical chemistry
protein–protein interactions
protein–DNA interactions
protein–ligand interactions
receptor–ligand interactions
biomolecular structure and function
protein folding and stability

Published Papers (7 papers)

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Research

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25 pages, 10551 KiB

Open AccessArticle

Predicting the Structure of Enzymes with Metal Cofactors: The Example of [FeFe] Hydrogenases

by Simone Botticelli, Giovanni La Penna, Velia Minicozzi, Francesco Stellato, Silvia Morante, Giancarlo Rossi and Cecilia Faraloni

Int. J. Mol. Sci. 2024, 25(7), 3663; https://doi.org/10.3390/ijms25073663 - 25 Mar 2024

Viewed by 552

Abstract

The advent of deep learning algorithms for protein folding opened a new era in the ability of predicting and optimizing the function of proteins once the sequence is known. The task is more intricate when cofactors like metal ions or small ligands are essential to functioning. In this case, the combined use of traditional simulation methods based on interatomic force fields and deep learning predictions is mandatory. We use the example of [FeFe] hydrogenases, enzymes of unicellular algae promising for biotechnology applications to illustrate this situation. [FeFe] hydrogenase is an iron–sulfur protein that catalyzes the chemical reduction of protons dissolved in liquid water into molecular hydrogen as a gas. Hydrogen production efficiency and cell sensitivity to dioxygen are important parameters to optimize the industrial applications of biological hydrogen production. Both parameters are related to the organization of iron–sulfur clusters within protein domains. In this work, we propose possible three-dimensional structures of Chlorella vulgaris 211/11P [FeFe] hydrogenase, the sequence of which was extracted from the recently published genome of the given strain. Initial structural models are built using: (i) the deep learning algorithm AlphaFold; (ii) the homology modeling server SwissModel; (iii) a manual construction based on the best known bacterial crystal structure. Missing iron–sulfur clusters are included and microsecond-long molecular dynamics of initial structures embedded into the water solution environment were performed. Multiple-walkers metadynamics was also used to enhance the sampling of structures encompassing both functional and non-functional organizations of iron–sulfur clusters. The resulting structural model provided by deep learning is consistent with functional [FeFe] hydrogenase characterized by peculiar interactions between cofactors and the protein matrix. Full article

(This article belongs to the Special Issue Biomolecular Structure, Function and Interactions)

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13 pages, 4332 KiB

Open AccessArticle

The Human Mutation K237_V238del in a Putative Lipid Binding Motif within the V-ATPase a2 Isoform Suggests a Molecular Mechanism Underlying Cutis Laxa

by Anh Chu, Yeqi Yao, Miroslawa Glibowicka, Charles M. Deber and Morris F. Manolson

Int. J. Mol. Sci. 2024, 25(4), 2170; https://doi.org/10.3390/ijms25042170 - 11 Feb 2024

Viewed by 579

Abstract

Vacuolar ATPases (V-ATPases), proton pumps composed of 16 subunits, are necessary for a variety of cellular functions. Subunit “a” has four isoforms, a1–a4, each with a distinct cellular location. We identified a phosphoinositide (PIP) interaction motif, KX_nK(R)IK(R), conserved in all four isoforms, and hypothesize that a/PIP interactions regulate V-ATPase recruitment/retention to different organelles. Among the four isoforms, a2 is enriched on Golgi with a2 mutations in the PIP motif resulting in cutis laxa. We hypothesize that the hydrophilic N-terminal (NT) domain of a2 contains a lipid-binding domain, and mutations in this domain prevent interaction with Golgi-enriched PIPs, resulting in cutis laxa. We recreated the cutis laxa-causing mutation K237_V238del, and a double mutation in the PIP-binding motif, K237A/V238A. Circular dichroism confirmed that there were no protein structure alterations. Pull-down assays with PIP-enriched liposomes revealed that wildtype a2NT preferentially binds phosphatidylinositol 4-phosphate (PI(4)P), while mutants decreased binding to PI(4)P. In HEK293 cells, wildtype a2NT was localized to Golgi and co-purified with microsomal membranes. Mutants reduced Golgi localization and membrane association. Rapamycin depletion of PI(4)P diminished a2NT-Golgi localization. We conclude that a2NT is sufficient for Golgi retention, suggesting the lipid-binding motif is involved in V-ATPase targeting and/or retention. Mutational analyses suggest a molecular mechanism underlying how a2 mutations result in cutis laxa. Full article

(This article belongs to the Special Issue Biomolecular Structure, Function and Interactions)

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12 pages, 3848 KiB

Open AccessArticle

Structural Insights into the Penicillin-Binding Protein 4 (DacB) from Mycobacterium tuberculosis

by Sung-Min Kang and Do-Hee Kim

Int. J. Mol. Sci. 2024, 25(2), 983; https://doi.org/10.3390/ijms25020983 - 12 Jan 2024

Viewed by 594

Abstract

Mycobacterium tuberculosis, a major cause of mortality from a single infectious agent, possesses a remarkable mycobacterial cell envelope. Penicillin-Binding Proteins (PBPs) are a family of bacterial enzymes involved in the biosynthesis of peptidoglycan. PBP4 (DacB) from M. tuberculosis (MtbPBP4) has been known to function as a carboxypeptidase, and the role and significance of carboxypeptidases as targets for anti-tuberculosis drugs or antibiotics have been extensively investigated over the past decade. However, their precise involvement remains incompletely understood. In this study, we employed predictive modeling and analyzed the three-dimensional structure of MtbPBP4. Interestingly, MtbPBP4 displayed a distinct domain structure compared to its homologs. Docking studies with meropenem verified the presence of active site residues conserved in PBPs. These findings establish a structural foundation for comprehending the molecular function of MtbPBP4 and offer a platform for the exploration of novel antibiotics. Full article

(This article belongs to the Special Issue Biomolecular Structure, Function and Interactions)

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17 pages, 1370 KiB

Open AccessArticle

Cortical and Striatal Astrocytes of Neonatal Rats Display Distinct Molecular and Pharmacological Characteristics of Dopamine Uptake

by Vesna Sočan, Klemen Dolinar and Mojca Kržan

Int. J. Mol. Sci. 2024, 25(2), 911; https://doi.org/10.3390/ijms25020911 - 11 Jan 2024

Viewed by 574

Abstract

Astrocytes are crucial in the regulation of neurotransmitter homeostasis, and while their involvement in the dopamine (DA) tripartite synapse is acknowledged, it necessitates a more comprehensive investigation. In the present study, experiments were conducted on primary astrocyte cultures from the striatum and cortex of neonatal rats. The pharmacological intricacies of DA uptake, including dependence on time, temperature, and concentration, were investigated using radiolabelled [³H]-DA. The mRNA expression of transporters DAT, NET, PMAT, and OCTs was evaluated by qPCR. Notably, astrocytes from both brain regions exhibited prominent mRNA expression of NET and PMAT, with comparatively lower expression of DAT and OCTs. The inhibition of DA uptake by the DAT inhibitor, GBR12909, and NET inhibitors, desipramine and nortriptyline, impeded DA uptake in striatal astrocytes more than in cortical astrocytes. The mRNA expression of NET and PMAT was significantly upregulated in cortical astrocytes in response to the DA receptor agonist apomorphine, while only the mRNA expression of NET exhibited changes in striatal astrocytes. Haloperidol, a DA receptor antagonist, and L-DOPA, a DA precursor, did not induce significant alterations in transporter mRNA expression. These findings underscore the intricate and region-specific mechanisms governing DA uptake in astrocytes, emphasizing the need for continued exploration to unravel the nuanced dynamics of astrocytic involvement in the DA tripartite synapse. Full article

(This article belongs to the Special Issue Biomolecular Structure, Function and Interactions)

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17 pages, 3927 KiB

Open AccessArticle

Evaluation of the Structure–Function Relationship of SGNH Lipase from Streptomyces rimosus by Site-Directed Mutagenesis and Computational Approach

by Želimira Filić, Ana Bielen, Ela Šarić, Mirsada Ćehić, Ivo Crnolatac, Sanja Tomić, Dušica Vujaklija and Marija Abramić

Int. J. Mol. Sci. 2024, 25(1), 595; https://doi.org/10.3390/ijms25010595 - 02 Jan 2024

Viewed by 759

Abstract

Streptomyces rimosus extracellular lipase (SrL) is a multifunctional hydrolase belonging to the SGNH family. Here site-directed mutagenesis (SDM) was used for the first time to investigate the functional significance of the conserved amino acid residues Ser10, Gly54, Asn82, Asn213, and His216 in the active site of SrL. The hydrolytic activity of SrL variants was determined using para-nitrophenyl (pNP) esters with C4, C8, and C16 fatty acid chains. Mutation of Ser10, Asn82, or His216, but not Gly54, to Ala abolished lipase activity for all substrates. In contrast, the Asn213Ala variant showed increased enzymatic activity for C8 and C16 pNP esters. Molecular dynamics (MD) simulations showed that the interactions between the long alkyl chain substrate (C16) and Ser10 and Asn82 were strongest in Asn213Ala SrL. In addition to Asn82, Gly54, and Ser10, several new constituents of the substrate binding site were recognized (Lys28, Ser53, Thr89, and Glu212), as well as strong electrostatic interactions between Lys28 and Glu212. In addition to the H bonds Ser10–His216 and His216–Ser214, Tyr11 interacted strongly with Ser10 and His216 in all complexes with an active enzyme form. A previously unknown strong H bond between the catalytically important Asn82 and Gly54 was uncovered, which stabilizes the substrate in an orientation suitable for the enzyme reaction. Full article

(This article belongs to the Special Issue Biomolecular Structure, Function and Interactions)

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17 pages, 2958 KiB

Open AccessArticle

Discovery and Visualization of the Hidden Relationships among N-Glycosylation, Disulfide Bonds, and Membrane Topology

by Manthan Desai, Amritpal Singh, David Pham, Syed Rafid Chowdhury and Bingyun Sun

Int. J. Mol. Sci. 2023, 24(22), 16182; https://doi.org/10.3390/ijms242216182 - 10 Nov 2023

Cited by 1 | Viewed by 805

Abstract

Membrane proteins (MPs) are functionally important but structurally complex. In particular, MPs often carry three structural features, i.e., transmembrane domains (TMs), disulfide bonds (SSs), and N-glycosylation (N-GLYCO). All three features have been intensively studied; however, how the three features potentially correlate has been less addressed in the literature. With the growing accuracy from computational prediction, we used publicly available information on SSs and N-GLYCO and analyzed the potential relationships among post-translational modifications (PTMs) and the predicted membrane topology in the human proteome. Our results suggested a very close relationship between SSs and N-GLYCO that behaved similarly, whereas a complementary relation between the TMs and the two PTMs was also revealed, in which the high SS and/or N-GLYCO presence is often accompanied by a low TM occurrence in a protein. Furthermore, the occurrence of SSs and N-GLYCO in a protein heavily relies on the protein length; however, TMs seem not to possess such length dependence. Finally, SSs exhibits larger potential dynamics than N-GLYCO, which is confined by the presence of sequons. The special classes of proteins possessing extreme or unique patterns of the three structural features are comprehensively identified, and their structural features and potential dynamics help to identify their susceptibility to different physiological and pathophysiological insults, which could help drug development and protein engineering. Full article

(This article belongs to the Special Issue Biomolecular Structure, Function and Interactions)

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Review

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20 pages, 3535 KiB

Open AccessReview

Structures, Mechanisms, and Physiological Functions of Zinc Transporters in Different Biological Kingdoms

by Han Ba Bui and Kenji Inaba

Int. J. Mol. Sci. 2024, 25(5), 3045; https://doi.org/10.3390/ijms25053045 - 06 Mar 2024

Viewed by 580

Abstract

Zinc transporters take up/release zinc ions (Zn²⁺) across biological membranes and maintain intracellular and intra-organellar Zn²⁺ homeostasis. Since this process requires a series of conformational changes in the transporters, detailed information about the structures of different reaction intermediates is required for a comprehensive understanding of their Zn²⁺ transport mechanisms. Recently, various Zn²⁺ transport systems have been identified in bacteria, yeasts, plants, and humans. Based on structural analyses of human ZnT7, human ZnT8, and bacterial YiiP, we propose updated models explaining their mechanisms of action to ensure efficient Zn²⁺ transport. We place particular focus on the mechanistic roles of the histidine-rich loop shared by several zinc transporters, which facilitates Zn²⁺ recruitment to the transmembrane Zn²⁺-binding site. This review provides an extensive overview of the structures, mechanisms, and physiological functions of zinc transporters in different biological kingdoms. Full article

(This article belongs to the Special Issue Biomolecular Structure, Function and Interactions)

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