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Biophysica, Volume 1, Issue 2 (June 2021) – 13 articles

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Article
Use of Magnetic Nanoparticles as In Situ Mucus Property Probe
Biophysica 2021, 1(2), 249-268; https://0-doi-org.brum.beds.ac.uk/10.3390/biophysica1020019 - 18 Jun 2021
Viewed by 230
Abstract
Magnetic nanoparticles (MNPs) are unique in their abilities to penetrate and interact with a wide range of liquid media. Because of their magnetic properties, MNPs can be directed to any area of interest, and interact with core structures deep inside the medium which [...] Read more.
Magnetic nanoparticles (MNPs) are unique in their abilities to penetrate and interact with a wide range of liquid media. Because of their magnetic properties, MNPs can be directed to any area of interest, and interact with core structures deep inside the medium which is normally inaccessible. In this report, we investigate the behavior of MNPs in a specific biological fluid, namely in a mucus layer of air–liquid interface cultured primary normal human tracheobronchial epithelial cells. Using Fokker–Planck algorithm simulations and observing the behavior of MNPs from prior experiments, we found MNPs that are initially less than 100 nm in size, to aggregate into sizes of ~50 μm and to deviate from the expected Fokker–Planck distribution due to the mucus structure. Based on our analysis, human tracheobronchial epithelial (NHTE) cell mucus viscosity ranges from 15 Pa·s to 150 Pa·s. The results not only confirm the possible use of MNPs as a means for medical drug delivery but also underline important consequences of MNP surface modifications. Full article
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Article
Modelling the Activation Pathways in Full-Length Src Kinase
Biophysica 2021, 1(2), 238-248; https://0-doi-org.brum.beds.ac.uk/10.3390/biophysica1020018 - 11 Jun 2021
Viewed by 493
Abstract
Src kinases play fundamental roles in several crucial cell processes. Their activity is tightly regulated by conformational transitions between the active and the inactive forms, which are carried out by complex protein structural rearrangements. Here, we present an in-depth study of such structural [...] Read more.
Src kinases play fundamental roles in several crucial cell processes. Their activity is tightly regulated by conformational transitions between the active and the inactive forms, which are carried out by complex protein structural rearrangements. Here, we present an in-depth study of such structural transitions coupling extensive all-atoms molecular dynamic simulations coupled to an algorithm able to drive the system between defined conformational states. Our results, in line with the available experimental data, confirm the complexity of such a process indicating the main molecular determinants involved. Moreover, the role of an Src inhibitor—able to bind to the protein inactive state—is discussed and compared with available experimental data. Full article
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Article
Selection of Unique Molecules for Cancer Treatment by Distance-Based Method: Hypericin Effect on Respiratory Chain
Biophysica 2021, 1(2), 222-237; https://0-doi-org.brum.beds.ac.uk/10.3390/biophysica1020017 - 08 Jun 2021
Viewed by 446
Abstract
The heterogeneous composition of tumors presents a significant obstacle to the selection of a single molecule as a potential universal inhibitor of tumor growth. Lipid signaling and cellular metabolism have become the main targets of anticancer treatment in recent years. The protein kinase [...] Read more.
The heterogeneous composition of tumors presents a significant obstacle to the selection of a single molecule as a potential universal inhibitor of tumor growth. Lipid signaling and cellular metabolism have become the main targets of anticancer treatment in recent years. The protein kinase C (PKC) regulators Gö6976, rottlerin, hypericin, and phorbol myristyl acetate have been identified as agents affecting cellular metabolism. Measurable parameters describing metabolism, endocytosis, and respiration were subjected to a distance-based computational procedure for higher dimensions to complement and extend the knowledge gained from experimental data. The mutual distances of the parameters of the substances applied to the cancer cells in the presence and absence of lipids were calculated within the Lp spaces. The distance-based methods and comparisons of the generalized distances suggested to us the exceptional role of hypericin in heterogeneous systems. Furthermore, our results are confirmed by Western blotting of the levels of respiratory chain proteins and enzymes active in oxidative stress defense in cancer cell monolayers and spheroids. PKCα and PKCδ have been studied for lipid-activated cell signaling. In this study, we attempt to apply the concept of parametric distance in cell signal transduction and activation where the above methods have not yet been used. Full article
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Article
The Dynamics of Subunit Rotation in a Eukaryotic Ribosome
Biophysica 2021, 1(2), 204-221; https://0-doi-org.brum.beds.ac.uk/10.3390/biophysica1020016 - 24 May 2021
Viewed by 674
Abstract
Protein synthesis by the ribosome is coordinated by an intricate series of large-scale conformational rearrangements. Structural studies can provide information about long-lived states, however biological kinetics are controlled by the intervening free-energy barriers. While there has been progress describing the energy landscapes of [...] Read more.
Protein synthesis by the ribosome is coordinated by an intricate series of large-scale conformational rearrangements. Structural studies can provide information about long-lived states, however biological kinetics are controlled by the intervening free-energy barriers. While there has been progress describing the energy landscapes of bacterial ribosomes, very little is known about the energetics of large-scale rearrangements in eukaryotic systems. To address this topic, we constructed an all-atom model with simplified energetics and performed simulations of subunit rotation in the yeast ribosome. In these simulations, the small subunit (SSU; ∼1 MDa) undergoes spontaneous and reversible rotation events (∼8). By enabling the simulation of this rearrangement under equilibrium conditions, these calculations provide initial insights into the molecular factors that control dynamics in eukaryotic ribosomes. Through this, we are able to identify specific inter-subunit interactions that have a pronounced influence on the rate-limiting free-energy barrier. We also show that, as a result of changes in molecular flexibility, the thermodynamic balance between the rotated and unrotated states is temperature-dependent. This effect may be interpreted in terms of differential molecular flexibility within the rotated and unrotated states. Together, these calculations provide a foundation, upon which the field may begin to dissect the energetics of these complex molecular machines. Full article
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Article
SARS-CoV-2 Spike-Derived Peptides Presented by HLA Molecules
Biophysica 2021, 1(2), 194-203; https://0-doi-org.brum.beds.ac.uk/10.3390/biophysica1020015 - 19 May 2021
Viewed by 1252
Abstract
The SARS-CoV-2 virus responsible for the COVID-19 pandemic has caused significant morbidity and mortality worldwide. With the remarkable advances in medical research, vaccines were developed to prime the human immune system and decrease disease severity. Despite these achievements, the fundamental basis of immunity [...] Read more.
The SARS-CoV-2 virus responsible for the COVID-19 pandemic has caused significant morbidity and mortality worldwide. With the remarkable advances in medical research, vaccines were developed to prime the human immune system and decrease disease severity. Despite these achievements, the fundamental basis of immunity to the SARS-CoV-2 virus is still largely undefined. Here, we solved the crystal structure of three spike-derived peptides presented by three different HLA molecules, and determined the stability of the overall peptide–HLA complexes formed. The peptide presentation of spike-derived peptides can influence the way in which CD8+ T cells can recognise infected cells, clear infection, and therefore, control the outcome of the disease. Full article
(This article belongs to the Special Issue Biophysical Advances in Structure-Based Drug Design)
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Article
Energy Dissipation Hypothesis Applied to Enhance the Affinity of Thrombin Binding Aptamer
Biophysica 2021, 1(2), 179-193; https://0-doi-org.brum.beds.ac.uk/10.3390/biophysica1020014 - 14 May 2021
Viewed by 388
Abstract
Nucleic acid aptamers are artificial recognizing molecules that are capable of specific binding to a wide variety of targets. Aptamers are commonly selected from a huge library of oligonucleotides and improved by introducing several mutations or modular constructions. Although aptamers hold great promise [...] Read more.
Nucleic acid aptamers are artificial recognizing molecules that are capable of specific binding to a wide variety of targets. Aptamers are commonly selected from a huge library of oligonucleotides and improved by introducing several mutations or modular constructions. Although aptamers hold great promise as therapeutic and diagnostic tools, no simple approach to improve their affinity has been suggested yet. Our recent analysis of aptamer–protein complexes revealed that aptamer affinity correlates with the size of an amino acid sidechain in the protein interface that was explained by efficient dissipation of the energy released during complex formation. G-quadruplex-based thrombin aptamers are not involved in the described dependence. Moreover, aptamers to the same thrombin site have 100-fold differences in affinity. Here we focused on a detailed analysis of the nucleic acid interface of thrombin–aptamer complexes. High affinity of the aptamers was shown to correlate with the solvent accessibility of the apolar part of recognizing loops. To prove the concept experimentally, these loops were modified to enhance contact with the solvent. Dissociation rates of the aptamer–thrombin complexes were drastically slowed due to these modifications. In full correspondence with the energy dissipation hypothesis, the modifications improved both the stability of the G-quadruplexes and affinity to thrombin. The most evident effect was shown for unstable Na+-coordinated G-quadruplexes. These data are of high interest for a directed improvement of aptamers introducing unnatural modifications into the ‘hot spot’ residues. Full article
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Article
Computational Assessment of Modified Antifreeze Glycoproteins on Ice Nucleation
Biophysica 2021, 1(2), 168-178; https://0-doi-org.brum.beds.ac.uk/10.3390/biophysica1020013 - 06 May 2021
Viewed by 476
Abstract
Antifreeze glycoproteins (AFGPs) found in various fish are used by the organisms to prevent freezing. While these compounds have been studied for their ability to bind to, and prevent the complete crystallization of water, the exact mechanisms by which AFGPs prevent freezing are [...] Read more.
Antifreeze glycoproteins (AFGPs) found in various fish are used by the organisms to prevent freezing. While these compounds have been studied for their ability to bind to, and prevent the complete crystallization of water, the exact mechanisms by which AFGPs prevent freezing are still undetermined. Therefore, building upon our previous work, this study uses molecular dynamics simulations to assess the effects of hydroxyl group separation distance on AFGP ice nucleation activity. Water droplet crystallization simulations showed that modified AFGP structures containing hydroxyl distances smaller than ~3.0 Å lost their ability to prevent ice crystallization. Furthermore, modified AFGP containing hydroxyl distances of 7.327 Å and 6.160 Å was correlated with a promotion in ice nucleation, as demonstrated by the changes in the energy of the system. This supports the notion that the distance, and therefore, geometry characteristics between the hydroxyl groups located on the saccharide structures play a key role in the ice crystallization inhibition properties of AFGP compounds. Full article
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Article
Probing Conformational Dynamics by Protein Contact Networks: Comparison with NMR Relaxation Studies and Molecular Dynamics Simulations
Biophysica 2021, 1(2), 157-167; https://0-doi-org.brum.beds.ac.uk/10.3390/biophysica1020012 - 08 Apr 2021
Viewed by 848
Abstract
Protein contact networks (PCNs) have been used for the study of protein structure and function for the past decade. In PCNs, each amino acid is considered as a node while the contacts among amino acids are the links/edges. We examined the possible correlation [...] Read more.
Protein contact networks (PCNs) have been used for the study of protein structure and function for the past decade. In PCNs, each amino acid is considered as a node while the contacts among amino acids are the links/edges. We examined the possible correlation between the closeness centrality measure of amino acids within PCNs and their mobility as known from NMR spin relaxation experiments and molecular dynamic (MD) simulations. The pivotal observation was that plasticity within a protein stretch correlated inversely to closeness centrality. Effects on protein conformational plasticity caused by the formation of disulfide bonds or protein–protein interactions were also identified by the PCN analysis measure closeness centrality and the hereby introduced percentage of closeness centrality perturbation (% CCP). All the comparisons between PCN measures, NMR data, and MDs were performed in a set of proteins of different biological functions and structures: the core protease domain of anthrax lethal factor, the N-terminal RING domain of E3 Ub ligase Arkadia, the reduced and oxidized forms of human thioredoxin 1, and the ubiquitin molecules (Ub) of the catalytic Ub–RING–E3–E2–Ub complex of E3 ligase Ark2.The graph theory analysis of PCNs could thus provide a general method for assessing the conformational dynamics of free proteins and putative plasticity changes between different protein forms (apo/complexed or reduced/oxidized). Full article
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Review
Amyloid-Mediated Mechanisms of Membrane Disruption
Biophysica 2021, 1(2), 137-156; https://0-doi-org.brum.beds.ac.uk/10.3390/biophysica1020011 - 07 Apr 2021
Viewed by 437
Abstract
Protein aggregation and amyloid formation are pathogenic events underlying the development of an increasingly large number of human diseases named “proteinopathies”. Abnormal accumulation in affected tissues of amyloid β (Aβ) peptide, islet amyloid polypeptide (IAPP), and the prion protein, to mention a few, [...] Read more.
Protein aggregation and amyloid formation are pathogenic events underlying the development of an increasingly large number of human diseases named “proteinopathies”. Abnormal accumulation in affected tissues of amyloid β (Aβ) peptide, islet amyloid polypeptide (IAPP), and the prion protein, to mention a few, are involved in the occurrence of Alzheimer’s (AD), type 2 diabetes mellitus (T2DM) and prion diseases, respectively. Many reports suggest that the toxic properties of amyloid aggregates are correlated with their ability to damage cell membranes. However, the molecular mechanisms causing toxic amyloid/membrane interactions are still far to be completely elucidated. This review aims at describing the mutual relationships linking abnormal protein conformational transition and self-assembly into amyloid aggregates with membrane damage. A cross-correlated analysis of all these closely intertwined factors is thought to provide valuable insights for a comprehensive molecular description of amyloid diseases and, in turn, the design of effective therapies. Full article
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Article
Cytotoxicity of Quillaja saponaria Saponins towards Lung Cells Is Higher for Cholesterol-Rich Cells
Biophysica 2021, 1(2), 126-136; https://0-doi-org.brum.beds.ac.uk/10.3390/biophysica1020010 - 06 Apr 2021
Viewed by 496
Abstract
The purpose of the study was to compare cytotoxicity of two Quillaja saponaria bark saponin (QBS) mixtures against two lung cell lines: normal MRC-5 fibroblast cell line and tumor A-549 epithelial cells of lungs’ alveoli. The study, performed both at a macro-scale and [...] Read more.
The purpose of the study was to compare cytotoxicity of two Quillaja saponaria bark saponin (QBS) mixtures against two lung cell lines: normal MRC-5 fibroblast cell line and tumor A-549 epithelial cells of lungs’ alveoli. The study, performed both at a macro-scale and in a dedicated microfluidic device, showed that QBS was more toxic to the cell line more abundant in cholesterol (MRC-5). The QBS mixture with higher saponin fraction was found to be more cytotoxic towards both cell lines. The results may help to better understand the cytotoxicity of saponin-rich herbal medicines towards normal and tumor cells depending on their cholesterol content. Full article
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Review
Probing Structural Dynamics of Membrane Proteins Using Electron Paramagnetic Resonance Spectroscopic Techniques
Biophysica 2021, 1(2), 106-125; https://0-doi-org.brum.beds.ac.uk/10.3390/biophysica1020009 - 30 Mar 2021
Viewed by 494
Abstract
Membrane proteins are essential for the survival of living organisms. They are involved in important biological functions including transportation of ions and molecules across the cell membrane and triggering the signaling pathways. They are targets of more than half of the modern medical [...] Read more.
Membrane proteins are essential for the survival of living organisms. They are involved in important biological functions including transportation of ions and molecules across the cell membrane and triggering the signaling pathways. They are targets of more than half of the modern medical drugs. Despite their biological significance, information about the structural dynamics of membrane proteins is lagging when compared to that of globular proteins. The major challenges with these systems are low expression yields and lack of appropriate solubilizing medium required for biophysical techniques. Electron paramagnetic resonance (EPR) spectroscopy coupled with site directed spin labeling (SDSL) is a rapidly growing powerful biophysical technique that can be used to obtain pertinent structural and dynamic information on membrane proteins. In this brief review, we will focus on the overview of the widely used EPR approaches and their emerging applications to answer structural and conformational dynamics related questions on important membrane protein systems. Full article
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Article
The Roles of Protein Structure, Taxon Sampling, and Model Complexity in Phylogenomics: A Case Study Focused on Early Animal Divergences
Biophysica 2021, 1(2), 87-105; https://0-doi-org.brum.beds.ac.uk/10.3390/biophysica1020008 - 25 Mar 2021
Viewed by 519
Abstract
Despite the long history of using protein sequences to infer the tree of life, the potential for different parts of protein structures to retain historical signal remains unclear. We propose that it might be possible to improve analyses of phylogenomic datasets by incorporating [...] Read more.
Despite the long history of using protein sequences to infer the tree of life, the potential for different parts of protein structures to retain historical signal remains unclear. We propose that it might be possible to improve analyses of phylogenomic datasets by incorporating information about protein structure. We test this idea using the position of the root of Metazoa (animals) as a model system. We examined the distribution of “strongly decisive” sites (alignment positions that support a specific tree topology) in a dataset comprising >1500 proteins and almost 100 taxa. The proportion of each class of strongly decisive sites in different structural environments was very sensitive to the model used to analyze the data when a limited number of taxa were used but they were stable when taxa were added. As long as enough taxa were analyzed, sites in all structural environments supported the same topology regardless of whether standard tree searches or decisive sites were used to select the optimal tree. However, the use of decisive sites revealed a difference between the support for minority topologies for sites in different structural environments: buried sites and sites in sheet and coil environments exhibited equal support for the minority topologies, whereas solvent-exposed and helix sites had unequal numbers of sites, supporting the minority topologies. This suggests that the relatively slowly evolving buried, sheet, and coil sites are giving an accurate picture of the true species tree and the amount of conflict among gene trees. Taken as a whole, this study indicates that phylogenetic analyses using sites in different structural environments can yield different topologies for the deepest branches in the animal tree of life and that analyzing larger numbers of taxa eliminates this conflict. More broadly, our results highlight the desirability of incorporating information about protein structure into phylogenomic analyses. Full article
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Article
Nanomarker for Early Detection of Alzheimer’s Disease Combining Ab initio DFT Simulations and Molecular Docking Approach
Biophysica 2021, 1(2), 76-86; https://0-doi-org.brum.beds.ac.uk/10.3390/biophysica1020007 - 24 Mar 2021
Viewed by 615
Abstract
The tau protein is considered an important qualitative and quantitative biomarker for Alzheimer’s disease in its asymptomatic phase. In 2011, biomarkers were suggested by the National Institute on Aging-Azheimer’s Association as a new criterion for the early diagnosis of Alzheimer’s disease. Thus, highlighting [...] Read more.
The tau protein is considered an important qualitative and quantitative biomarker for Alzheimer’s disease in its asymptomatic phase. In 2011, biomarkers were suggested by the National Institute on Aging-Azheimer’s Association as a new criterion for the early diagnosis of Alzheimer’s disease. Thus, highlighting the non-existence of theoretical research on the subject, we investigated the binding interaction properties between phosphorylated tau protein and a theoretically modeled ligands constituted by the fullerol functionalized with radiopharmaceuticals from an in silico approach via molecular docking and density functional theory (DFT) ab initio computational simulation. The results demonstrated that the ligand with the greatest affinity-based binding energy to the protein was fullerol + F-THK5105. However, all systems were considered promising for the development of a potential diagnostic nanomarker. These theoretical results could efficiently contribute to reduce the time and the cost for future experimental preclinical studies and open new opportunities toward molecular recognition in nanomedicine. Full article
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