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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 December 2023) | Viewed by 10064

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Dr. Andrei-José Petrescu

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Guest Editor

Department of Bioinformatics and Structural Biochemistry, Splaiul Independentei 296, 060031 Bucharest 17, Romania
Interests: molecular biophysics; physics techniques in biochemistry; molecular modelaing; simulation; glycobiology

Prof. Dr. Dan Florin Mihǎilescu

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Guest Editor

Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania
Interests: molecular modeling; QSAR; bovine serum albumin; THz spectroscopy; computitional mutagenesis

Dr. Maria Alexandra Mernea

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Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Romania
Interests: molecular modeling; molecular dynamics simulations; modeling of biomolecules and their interactions
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Special Issue Information

Dear Colleagues,

Membrane proteins are found in plasma membranes, in the membranes of cellular organelles or in the envelopes of viruses. These mediate key processes for cell function like membrane transport, signal transduction, cell recognition, cell adhesion or enzymatic reactions, thus representing important drug targets. Also, changes in membrane proteins represent biomarkers for diagnosis and prognostic in different pathogenic conditions. Such proteins present particular structures comprising transmembrane domains that strongly interact with surrounding lipids which stabilize them and even modulate their function and hydrophilic extracellular and/or intracellular regions that interact with the surrounding aqueous environment. The partitioning of membrane proteins in both lipid and water media is what makes the structural investigation of membrane proteins technologically challenging, especially in the field of sample preparation. Several strategies have improved this process, including the usage of recombinant proteins in the case of membrane proteins difficult to obtain from natural sources, screening of constructs from different species in order to identify the most stable and most suitable construct for structural studies, stabilization of protein structure using genetic engineering, encapsulation agents, ligands or chaperones. In addition, improvement of experimental methods, data collection and analysis has led to an increase in the structural information on membrane proteins and in the number of membrane protein structures deposited in databases.

In this special issue focused on the structural biology of membrane proteins we welcome experimental studies involving the usage of different techniques, as well as simulation studies that bring insight into the structure of membrane proteins.

Dr. Andrei-José Petrescu
Prof. Dr. Dan Florin Mihǎilescu
Dr. Maria Alexandra Mernea
Guest Editors

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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.

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

membrane protein structure
functional domains
protein-lipid interactions
protein-drug interaction
membrane protein structural models

Published Papers (5 papers)

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Research

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18 pages, 14222 KiB

Open AccessArticle

Gamma-Hemolysin Components: Computational Strategies for LukF-Hlg2 Dimer Reconstruction on a Model Membrane

by Costanza Paternoster, Thomas Tarenzi, Raffaello Potestio and Gianluca Lattanzi

Int. J. Mol. Sci. 2023, 24(8), 7113; https://doi.org/10.3390/ijms24087113 - 12 Apr 2023

Viewed by 1346

Abstract

The gamma-hemolysin protein is one of the most common pore-forming toxins expressed by the pathogenic bacterium Staphylococcus aureus. The toxin is used by the pathogen to escape the immune system of the host organism, by assembling into octameric transmembrane pores on the surface of the target immune cell and leading to its death by leakage or apoptosis. Despite the high potential risks associated with Staphylococcus aureus infections and the urgent need for new treatments, several aspects of the pore-formation process from gamma-hemolysin are still unclear. These include the identification of the interactions between the individual monomers that lead to the formation of a dimer on the cell membrane, which represents the unit for further oligomerization. Here, we employed a combination of all-atom explicit solvent molecular dynamics simulations and protein–protein docking to determine the stabilizing contacts that guide the formation of a functional dimer. The simulations and the molecular modeling reveal the importance of the flexibility of specific protein domains, in particular the N-terminus, to drive the formation of the correct dimerization interface through functional contacts between the monomers. The results obtained are compared with the experimental data available in the literature. Full article

(This article belongs to the Special Issue Structural Biology of Membrane Proteins)

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13 pages, 1822 KiB

Open AccessArticle

Unfolding Individual Domains of BmrA, a Bacterial ABC Transporter Involved in Multidrug Resistance

by Kristin Oepen, Veronika Mater and Dirk Schneider

Int. J. Mol. Sci. 2023, 24(6), 5239; https://doi.org/10.3390/ijms24065239 - 09 Mar 2023

Cited by 1 | Viewed by 1082

Abstract

The folding and stability of proteins are often studied via unfolding (and refolding) a protein with urea. Yet, in the case of membrane integral protein domains, which are shielded by a membrane or a membrane mimetic, urea generally does not induce unfolding. However, the unfolding of α-helical membrane proteins may be induced by the addition of sodium dodecyl sulfate (SDS). When protein unfolding is followed via monitoring changes in Trp fluorescence characteristics, the contributions of individual Trp residues often cannot be disentangled, and, consequently, the folding and stability of the individual domains of a multi-domain membrane protein cannot be studied. In this study, the unfolding of the homodimeric bacterial ATP-binding cassette (ABC) transporter Bacillus multidrug resistance ATP (BmrA), which comprises a transmembrane domain and a cytosolic nucleotide-binding domain, was investigated. To study the stability of individual BmrA domains in the context of the full-length protein, the individual domains were silenced by mutating the existent Trps. The SDS-induced unfolding of the corresponding constructs was compared to the (un)folding characteristics of the wild-type (wt) protein and isolated domains. The full-length variants BmrA_W413Y and BmrA_W104YW164A were able to mirror the changes observed with the isolated domains; thus, these variants allowed for the study of the unfolding and thermodynamic stability of mutated domains in the context of full-length BmrA. Full article

(This article belongs to the Special Issue Structural Biology of Membrane Proteins)

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18 pages, 1769 KiB

Open AccessArticle

Biochemical and Biophysical Characterization of the Caveolin-2 Interaction with Membranes and Analysis of the Protein Structural Alteration by the Presence of Cholesterol

by Berta Gorospe, José J. G. Moura, Carlos Gutierrez-Merino and Alejandro K. Samhan-Arias

Int. J. Mol. Sci. 2022, 23(23), 15203; https://doi.org/10.3390/ijms232315203 - 02 Dec 2022

Cited by 1 | Viewed by 1329

Abstract

Caveolin-2 is a protein suitable for the study of interactions of caveolins with other proteins and lipids present in caveolar lipid rafts. Caveolin-2 has a lower tendency to associate with high molecular weight oligomers than caveolin-1, facilitating the study of its structural modulation upon association with other proteins or lipids. In this paper, we have successfully expressed and purified recombinant human caveolin-2 using E. coli. The structural changes of caveolin-2 upon interaction with a lipid bilayer of liposomes were characterized using bioinformatic prediction models, circular dichroism, differential scanning calorimetry, and fluorescence techniques. Our data support that caveolin-2 binds and alters cholesterol-rich domains in the membranes through a CARC domain, a type of cholesterol-interacting domain in its sequence. The far UV-CD spectra support that the purified protein keeps its folding properties but undergoes a change in its secondary structure in the presence of lipids that correlates with the acquisition of a more stable conformation, as shown by differential scanning calorimetry experiments. Fluorescence experiments using egg yolk lecithin large unilamellar vesicles loaded with 1,6-diphenylhexatriene confirmed that caveolin-2 adsorbs to the membrane but only penetrates the core of the phospholipid bilayer if vesicles are supplemented with 30% of cholesterol. Our study sheds light on the caveolin-2 interaction with lipids. In addition, we propose that purified recombinant caveolin-2 can provide a new tool to study protein–lipid interactions within caveolae. Full article

(This article belongs to the Special Issue Structural Biology of Membrane Proteins)

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Review

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23 pages, 5876 KiB

Open AccessReview

Function Investigations and Applications of Membrane Proteins on Artificial Lipid Membranes

by Toshiyuki Tosaka and Koki Kamiya

Int. J. Mol. Sci. 2023, 24(8), 7231; https://doi.org/10.3390/ijms24087231 - 13 Apr 2023

Cited by 6 | Viewed by 3224

Abstract

Membrane proteins play an important role in key cellular functions, such as signal transduction, apoptosis, and metabolism. Therefore, structural and functional studies of these proteins are essential in fields such as fundamental biology, medical science, pharmacology, biotechnology, and bioengineering. However, observing the precise elemental reactions and structures of membrane proteins is difficult, despite their functioning through interactions with various biomolecules in living cells. To investigate these properties, methodologies have been developed to study the functions of membrane proteins that have been purified from biological cells. In this paper, we introduce various methods for creating liposomes or lipid vesicles, from conventional to recent approaches, as well as techniques for reconstituting membrane proteins into artificial membranes. We also cover the different types of artificial membranes that can be used to observe the functions of reconstituted membrane proteins, including their structure, number of transmembrane domains, and functional type. Finally, we discuss the reconstitution of membrane proteins using a cell-free synthesis system and the reconstitution and function of multiple membrane proteins. Full article

(This article belongs to the Special Issue Structural Biology of Membrane Proteins)

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21 pages, 2059 KiB

Open AccessReview

Structural and Functional Diversity of Two ATP-Driven Plant Proton Pumps

by Katarzyna Kabała and Małgorzata Janicka

Int. J. Mol. Sci. 2023, 24(5), 4512; https://doi.org/10.3390/ijms24054512 - 24 Feb 2023

Cited by 5 | Viewed by 2244

Abstract

Two ATP-dependent proton pumps function in plant cells. Plasma membrane H⁺-ATPase (PM H⁺-ATPase) transfers protons from the cytoplasm to the apoplast, while vacuolar H⁺-ATPase (V-ATPase), located in tonoplasts and other endomembranes, is responsible for proton pumping into the organelle lumen. Both enzymes belong to two different families of proteins and, therefore, differ significantly in their structure and mechanism of action. The plasma membrane H⁺-ATPase is a member of the P-ATPases that undergo conformational changes, associated with two distinct E1 and E2 states, and autophosphorylation during the catalytic cycle. The vacuolar H⁺-ATPase represents rotary enzymes functioning as a molecular motor. The plant V-ATPase consists of thirteen different subunits organized into two subcomplexes, the peripheral V₁ and the membrane-embedded V₀, in which the stator and rotor parts have been distinguished. In contrast, the plant plasma membrane proton pump is a functional single polypeptide chain. However, when the enzyme is active, it transforms into a large twelve-protein complex of six H⁺-ATPase molecules and six 14-3-3 proteins. Despite these differences, both proton pumps can be regulated by the same mechanisms (such as reversible phosphorylation) and, in some processes, such as cytosolic pH regulation, may act in a coordinated way. Full article

(This article belongs to the Special Issue Structural Biology of Membrane Proteins)

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