International Journal of Molecular Sciences

Editorial

Jump to: Research

3 pages, 175 KiB

Open AccessEditorial

State-of-the-Art Molecular Biophysics in Russia

by Oxana V. Galzitskaya

Int. J. Mol. Sci. 2024, 25(7), 3565; https://doi.org/10.3390/ijms25073565 - 22 Mar 2024

Viewed by 469

Abstract

Thirty years ago, scientists’ attention was focused on studying individual molecules, as well as their structure and function [...] Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Biophysics in Russia)

Research

Jump to: Editorial

0 pages, 3038 KiB

Open AccessArticle

The Structure and Nucleotide-Binding Characteristics of Regulated Cystathionine β-Synthase Domain-Containing Pyrophosphatase without One Catalytic Domain

by Ilya M. Zamakhov, Viktor A. Anashkin, Andrey V. Moiseenko, Victor N. Orlov, Natalia N. Vorobyeva, Olga S. Sokolova and Alexander A. Baykov

Int. J. Mol. Sci. 2023, 24(24), 17160; https://doi.org/10.3390/ijms242417160 - 5 Dec 2023

Cited by 1 | Viewed by 775

Abstract

Regulatory adenine nucleotide-binding cystathionine β-synthase (CBS) domains are widespread in proteins; however, information on the mechanism of their modulating effects on protein function is scarce. The difficulty in obtaining structural data for such proteins is ascribed to their unusual flexibility and propensity to [...] Read more.

Regulatory adenine nucleotide-binding cystathionine β-synthase (CBS) domains are widespread in proteins; however, information on the mechanism of their modulating effects on protein function is scarce. The difficulty in obtaining structural data for such proteins is ascribed to their unusual flexibility and propensity to form higher-order oligomeric structures. In this study, we deleted the most movable domain from the catalytic part of a CBS domain-containing bacterial inorganic pyrophosphatase (CBS-PPase) and characterized the deletion variant both structurally and functionally. The truncated CBS-PPase was inactive but retained the homotetrameric structure of the full-size enzyme and its ability to bind a fluorescent AMP analog (inhibitor) and diadenosine tetraphosphate (activator) with the same or greater affinity. The deletion stabilized the protein structure against thermal unfolding, suggesting that the deleted domain destabilizes the structure in the full-size protein. A “linear” 3D structure with an unusual type of domain swapping predicted for the truncated CBS-PPase by Alphafold2 was confirmed by single-particle electron microscopy. The results suggest a dual role for the CBS domains in CBS-PPase regulation: they allow for enzyme tetramerization, which impedes the motion of one catalytic domain, and bind adenine nucleotides to mitigate or aggravate this effect. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Biophysics in Russia)

► Show Figures

Graphical abstract

8 pages, 991 KiB

Open AccessCommunication

Registration of Functioning of a Single Horseradish Peroxidase Macromolecule with a Solid-State Nanopore

by Yuri D. Ivanov, Alexander N. Ableev, Ivan D. Shumov, Irina A. Ivanova, Nikita V. Vaulin, Denis V. Lebedev, Anton S. Bukatin, Ivan S. Mukhin and Alexander I. Archakov

Int. J. Mol. Sci. 2023, 24(21), 15636; https://doi.org/10.3390/ijms242115636 - 27 Oct 2023

Cited by 1 | Viewed by 811

Abstract

Currently, nanopore-based technology for the determination of the functional activity of single enzyme molecules continues its development. The use of natural nanopores for studying single enzyme molecules is known. At that, the approach utilizing artificial solid-state nanopores is also promising but still understudied. [...] Read more.

Currently, nanopore-based technology for the determination of the functional activity of single enzyme molecules continues its development. The use of natural nanopores for studying single enzyme molecules is known. At that, the approach utilizing artificial solid-state nanopores is also promising but still understudied. Herein, we demonstrate the use of a nanotechnology-based approach for the investigation of the enzymatic activity of a single molecule of horseradish peroxidase with a solid-state nanopore. The artificial 5 nm solid-state nanopore has been formed in a 40 nm thick silicon nitride structure. A single molecule of HRP has been entrapped into the nanopore. The activity of the horseradish peroxidase (HRP) enzyme molecule inserted in the nanopore has been monitored by recording the time dependence of the ion current through the nanopore in the course of the reaction of 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) oxidation reaction. We have found that in the process of ABTS oxidation in the presence of 2.5 mM hydrogen peroxide, individual HRP enzyme molecules are able to retain activity for approximately 700 s before a decrease in the ion current through the nanopore, which can be explained by structural changes of the enzyme. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Biophysics in Russia)

► Show Figures

Figure 1

12 pages, 2220 KiB

Open AccessArticle

Short Peptides of Innate Immunity Protein Tag7 (PGLYRP1) Selectively Induce Inhibition or Activation of Tumor Cell Death via TNF Receptor

by Daria M. Yurkina, Tatiana N. Sharapova, Elena A. Romanova, Denis V. Yashin and Lidia P. Sashchenko

Int. J. Mol. Sci. 2023, 24(14), 11363; https://doi.org/10.3390/ijms241411363 - 12 Jul 2023

Cited by 3 | Viewed by 1074

Abstract

In this study, we have found two peptides of Tag7 (PGLYRP1) protein-17.1A (HRDVQRT) and 17.1B (RSNYVLKG), that have different affinities to the TNFR1 receptor and the Hsp70 protein. Peptide 17.1A is able to inhibit signal transduction through the TNFR1 receptor, and peptide 17.1B [...] Read more.

In this study, we have found two peptides of Tag7 (PGLYRP1) protein-17.1A (HRDVQRT) and 17.1B (RSNYVLKG), that have different affinities to the TNFR1 receptor and the Hsp70 protein. Peptide 17.1A is able to inhibit signal transduction through the TNFR1 receptor, and peptide 17.1B can activate this receptor in a complex with Hsp70. Thus, it is possible to modulate the activity of the TNFR1 receptor and further perform its specific inhibition or activation in the treatment of various autoimmune or oncological diseases. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Biophysics in Russia)

► Show Figures

Graphical abstract

10 pages, 1580 KiB

Open AccessArticle

The Mechanism of Selective Recognition of Lipid Substrate by hDHHC20 Enzyme

by Irina S. Panina, Nikolay A. Krylov, Anton O. Chugunov, Roman G. Efremov and Larisa V. Kordyukova

Int. J. Mol. Sci. 2022, 23(23), 14791; https://doi.org/10.3390/ijms232314791 - 26 Nov 2022

Cited by 1 | Viewed by 1488

Abstract

S-acylation is a post-translational linkage of long chain fatty acids to cysteines, playing a key role in normal physiology and disease. In human cells, the reaction is catalyzed by a family of 23 membrane DHHC-acyltransferases (carrying an Asp-His-His-Cys catalytic motif) in two stages: [...] Read more.

S-acylation is a post-translational linkage of long chain fatty acids to cysteines, playing a key role in normal physiology and disease. In human cells, the reaction is catalyzed by a family of 23 membrane DHHC-acyltransferases (carrying an Asp-His-His-Cys catalytic motif) in two stages: (1) acyl-CoA-mediated autoacylation of the enzyme; and (2) further transfer of the acyl chain to a protein substrate. Despite the availability of a 3D-structure of human acyltransferase (hDHHC20), the molecular aspects of lipid selectivity of DHHC-acyltransferases remain unclear. In this paper, using molecular dynamics (MD) simulations, we studied membrane-bound hDHHC20 right before the acylation by C12-, C14-, C16-, C18-, and C20-CoA substrates. We found that: (1) regardless of the chain length, its terminal methyl group always reaches the “ceiling” of the enzyme’s cavity; (2) only for C16, an optimal “reactivity” (assessed by a simple geometric criterion) permits the autoacylation; (3) in MD, some key interactions between an acyl-CoA and a protein differ from those in the reference crystal structure of the C16-CoA-hDHHS20 mutant complex (probably, because this structure corresponds to a non-native dimer). These features of specific recognition of full-size acyl-CoA substrates support our previous hypothesis of “geometric and physicochemical selectivity” derived for simplified acyl-CoA analogues. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Biophysics in Russia)

► Show Figures

Figure 1

17 pages, 2473 KiB

Open AccessArticle

The Increased Amyloidogenicity of Spike RBD and pH-Dependent Binding to ACE2 May Contribute to the Transmissibility and Pathogenic Properties of SARS-CoV-2 Omicron as Suggested by In Silico Study

by Anna Y. Aksenova, Ilya V. Likhachev, Sergei Y. Grishin and Oxana V. Galzitskaya

Int. J. Mol. Sci. 2022, 23(21), 13502; https://doi.org/10.3390/ijms232113502 - 4 Nov 2022

Cited by 9 | Viewed by 3049

Abstract

SARS-CoV-2 is a rapidly evolving pathogen that has caused a global pandemic characterized by several consecutive waves. Based on epidemiological and NGS data, many different variants of SARS-CoV-2 were described and characterized since the original variant emerged in Wuhan in 2019. Notably, SARS-CoV-2 [...] Read more.

SARS-CoV-2 is a rapidly evolving pathogen that has caused a global pandemic characterized by several consecutive waves. Based on epidemiological and NGS data, many different variants of SARS-CoV-2 were described and characterized since the original variant emerged in Wuhan in 2019. Notably, SARS-CoV-2 variants differ in transmissibility and pathogenicity in the human population, although the molecular basis for this difference is still debatable. A significant role is attributed to amino acid changes in the binding surface of the Spike protein to the ACE2 receptor, which may facilitate virus entry into the cell or contribute to immune evasion. We modeled in silico the interaction between Spike RBDs of Wuhan-Hu-1, Delta, and Omicron BA.1 variants and ACE2 at different pHs (pH 5 and pH 7) and showed that the strength of this interaction was higher for the Omicron BA.1 RBD compared to Wuhan-Hu-1 or Delta RBDs and that the effect was more profound at pH 5. This finding is strikingly related to the increased ability of Omicron variants to spread in the population. We also noted that during its spread in the population, SARS-CoV-2 evolved to a more charged, basic composition. We hypothesize that the more basic surface of the Omicron variant may facilitate its spread in the upper respiratory tract but not in the lower respiratory tract, where pH estimates are different. We calculated the amyloidogenic properties of Spike RBDs in different SARS-CoV-2 variants and found eight amyloidogenic regions in the Spike RBDs for each of the variants predicted by the FoldAmyloid program. Although all eight regions were almost identical in the Wuhan to Gamma variants, two of them were significantly longer in both Omicron variants, making the Omicron RBD more amyloidogenic. We discuss how the increased predicted amyloidogenicity of the Omicron variants RBDs may be important for protein stability, influence its interaction with ACE2 and contribute to immune evasion. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Biophysics in Russia)

► Show Figures

Figure 1

19 pages, 5151 KiB

Open AccessArticle

Theoretical Explanation for the Rarity of Antibody-Dependent Enhancement of Infection (ADE) in COVID-19

by Anna E. Boldova, Julia D. Korobkin, Yury D. Nechipurenko and Anastasia N. Sveshnikova

Int. J. Mol. Sci. 2022, 23(19), 11364; https://doi.org/10.3390/ijms231911364 - 26 Sep 2022

Cited by 2 | Viewed by 2068

Abstract

Global vaccination against the SARS-CoV-2 virus has proved to be highly effective. However, the possibility of antibody-dependent enhancement of infection (ADE) upon vaccination remains underinvestigated. Here, we aimed to theoretically determine conditions for the occurrence of ADE in COVID-19. We developed a series [...] Read more.

Global vaccination against the SARS-CoV-2 virus has proved to be highly effective. However, the possibility of antibody-dependent enhancement of infection (ADE) upon vaccination remains underinvestigated. Here, we aimed to theoretically determine conditions for the occurrence of ADE in COVID-19. We developed a series of mathematical models of antibody response: model Ab—a model of antibody formation; model Cv—a model of infection spread in the body; and a complete model, which combines the two others. The models describe experimental data on SARS-CoV and SARS-CoV-2 infections in humans and cell cultures, including viral load dynamics, seroconversion times and antibody concentration kinetics. The modelling revealed that a significant proportion of macrophages can become infected only if they bind antibodies with high probability. Thus, a high probability of macrophage infection and a sufficient amount of pre-existing antibodies are necessary for the development of ADE in SARS-CoV-2 infection. However, from the point of view of the dynamics of pneumocyte infection, the two cases where the body has a high concentration of preexisting antibodies and a high probability of macrophage infection and where there is a low concentration of antibodies in the body and no macrophage infection are indistinguishable. This conclusion could explain the lack of confirmed ADE cases for COVID-19. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Biophysics in Russia)

► Show Figures

Figure 1

11 pages, 4318 KiB

Open AccessArticle

Electrostatic Map of the SARS-CoV-2 Virion Specifies Binding Sites of the Antiviral Cationic Photosensitizer

by Vladimir Fedorov, Ekaterina Kholina, Sergei Khruschev, Ilya Kovalenko, Andrew Rubin and Marina Strakhovskaya

Int. J. Mol. Sci. 2022, 23(13), 7304; https://doi.org/10.3390/ijms23137304 - 30 Jun 2022

Cited by 7 | Viewed by 2336

Abstract

Electrostatics is an important part of virus life. Understanding the detailed distribution of charges over the surface of a virus is important to predict its interactions with host cells, antibodies, drugs, and different materials. Using a coarse-grained model of the entire viral envelope [...] Read more.

Electrostatics is an important part of virus life. Understanding the detailed distribution of charges over the surface of a virus is important to predict its interactions with host cells, antibodies, drugs, and different materials. Using a coarse-grained model of the entire viral envelope developed by D. Korkin and S.-J. Marrink’s scientific groups, we created an electrostatic map of the external surface of SARS-CoV-2 and found a highly heterogeneous distribution of the electrostatic potential field of the viral envelope. Numerous negative patches originate mainly from negatively charged lipid domains in the viral membrane and negatively charged areas on the “stalks” of the spike (S) proteins. Membrane (M) and envelope (E) proteins with the total positive charge tend to colocalize with the negatively charged lipids. In the E protein pentamer exposed to the outer surface, negatively charged glutamate residues and surrounding lipids form a negative electrostatic potential ring around the channel entrance. We simulated the interaction of the antiviral octacationic photosensitizer octakis(cholinyl)zinc phthalocyanine with the surface structures of the entire model virion using the Brownian dynamics computational method implemented in ProKSim software (version r661). All mentioned negatively charged envelope components attracted the photosensitizer molecules and are thus potential targets for reactive oxygen generated in photosensitized reactions. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Biophysics in Russia)

► Show Figures