Latest articles in this journal
Published: 20 March 2023
Biophysica, Volume 3, pp 214-230; https://doi.org/10.3390/biophysica3010014
Zinc ions are the second most abundant ions found in humans. Their role in proteins can be merely structural but also catalytic, owing to their transition metal character. Modelling their geometric–coordination versatility by empirical force fields is, thus, a challenging task. In this work, we evaluated three popular models, specifically designed to represent zinc ions with regard to their capability of preserving structural integrity. To this end, we performed molecular dynamics simulations of two zinc-containing protein–DNA complexes, which differed in their zinc coordination, i.e., four cysteines or two cysteines and two histidines. The most flexible non-bonded 12-6-4 Lennard–Jones-type model shows a preference for six-fold coordination of the Zn
-ions in contradiction to the crystal structure. The cationic dummy atom model favours tetrahedral geometry, whereas the bonded extended zinc AMBER force field model, by construction, best preserves the initial geometry of a regular or slightly distorted tetrahedron. Our data renders the extended zinc AMBER force field the best model for structural zinc ions in a given geometry. In more complicated cases, though, more flexible models may be advantageous.
Published: 14 March 2023
Biophysica, Volume 3, pp 203-213; https://doi.org/10.3390/biophysica3010013
People’s lives and health are gravely threatened by non-small-cell lung cancer (NSCLC). Mutations in epidermal growth factor receptor (EGFR), a transmembrane receptor tyrosine kinase, are considered one of the causes of NSCLC. Tyrosine kinase inhibitors (TKIs) are typically used to treat patients with EGFR mutations. In this study, Gefitinib, a member of the first generation of TKIs, was used to treat an EGFR single-point mutation (single mutant, SM). Patients harboring additional T790M mutations in the kinase domain of the EGFR were resistant to Gefitinib. Then, the L858R/T790M double mutation (double mutant, DM) was treated with the second generation of TKIs, such as Afatinib. Here, we constructed four computational models to uncover the structural basis between EGFR mutants (SM and DM) and corresponding inhibitors (Gefitinib and Afatinib). The binding energy in the G-SM (representing Gefitinib in complex with SM) system was larger than that in the G-DM (Representing Gefitinib in complex with DM) system. Gefitinib’s affinity with L792 and M793 was drastically reduced by the longer side chain of M790 in the G-DM system, which pushed Gefitinib outside of the pocket. Additionally, the A-DM system’s binding energy was higher than the G-DM system’s. Afatinib, unlike Gefitinib, induced the P-loop region to move downwards to decrease the pocket entrance size to accommodate Afatinib properly and stably in the A-DM (Afatinib in complex with DM) system. These results uncover the details of interactions between EGFR and its inhibitors and shed light on the design of new tyrosine kinase inhibitors.
Published: 10 March 2023
Biophysica, Volume 3, pp 181-202; https://doi.org/10.3390/biophysica3010012
Neuronal cultures are one of the most important experimental models in modern interdisciplinary neuroscience, allowing to investigate in a control environment the emergence of complex behavior from an ensemble of interconnected neurons. Here, I review the research that we have conducted at the neurophysics laboratory at the University of Barcelona over the last 15 years, describing first the neuronal cultures that we prepare and the associated tools to acquire and analyze data, to next delve into the different research projects in which we actively participated to progress in the understanding of open questions, extend neuroscience research on new paradigms, and advance the treatment of neurological disorders. I finish the review by discussing the drawbacks and limitations of neuronal cultures, particularly in the context of brain-like models and biomedicine.
Published: 2 March 2023
Biophysica, Volume 3, pp 158-180; https://doi.org/10.3390/biophysica3010011
In recent years, sphingolipids have attracted significant attention due to their pivotal role in cellular functions and physiological diseases. A valuable tool for investigating the characteristics of sphingolipids can be represented via FT-IR spectroscopy, generally recognized as a very powerful technique that provides detailed biochemical information on the examined sample with the unique properties of sensitivity and accuracy. In the present paper, some fundamental aspects of sphingolipid components of human cells are summarized, and the most relevant articles devoted to the FT-IR spectroscopic studies of sphingolipids are revised. A short description of different FT-IR experimental approaches adopted for investigating sphingolipids is also given, with details about the most commonly used data analysis procedures. The present overview of FT-IR investigations, although not exhaustive, attests to the relevant role this vibrational technique has played in giving significant insight into many aspects of this fascinating class of lipids.
Published: 1 March 2023
Biophysica, Volume 3, pp 139-157; https://doi.org/10.3390/biophysica3010010
The active site of the dimeric ribose 5-phosphate isomerase B (RpiB) contains a solvent-exposed barrier formed by residues H12, R113, R137, and R141, which is closed upon the complexation of phosphate. The substrate ribose 5-phosphate (R5P) has to overcome the surface barrier to reach an internal cavity and then bind in the linear configuration of ribose to the interface between the two subunits. NMR and molecular dynamics simulation are suitable methods to describe the transient nature of the RpiB active site and help our understanding of the mechanism of substrate entrance. In this study, we show that the entrance of the nucleotides AMP/ADP into the internal cavity of mycobacterium tuberculosis RpiB (MtRpiB) does not involve a canonical open/close-lid conformational transition usually observed in many enzymes. Instead, a flipping mechanism in which the nucleotide phosphate interacts with the surface barrier followed by the flip of the nitrogenous base and ribose is responsible for changing the substrate/ligand orientation from a solvent-exposed to a buried state. Based on these results, we propose a substrate/inhibitor uptake mechanism that could provide a basis for rational drug design using MtRpiB, which is an essential enzyme and a good target for drug development.
Published: 28 February 2023
Biophysica, Volume 3, pp 121-138; https://doi.org/10.3390/biophysica3010009
The interaction of many peptides with lipid bilayer membranes strongly depends on the lipid composition. Here, a study of the impact of unsaturated lipid acyl chains on the interaction of a derivative of the HIV-1 fusion peptide with lipid bilayer vesicles is presented. Lipid bilayer vesicles composed of mixtures of lipids with two saturated acyl chains and lipids and one saturated and one unsaturated acyl chain, but identical head groups, were studied. The dependence of the peptide conformation on the unsaturated lipid content was probed by circular dichroism spectroscopy, while the impact of the peptide on the bilayer structure was determined by small-angle neutron scattering. The impact of the peptide on the lipid bilayer vesicle dynamics was investigated using neutron spin echo spectroscopy. Molecular dynamics simulations were used to characterize the behavior of the systems studied to determine if there were clear differences in their physical properties. The results reveal that the peptide–bilayer interaction is not a simple function of the unsaturated lipid acyl chain content of the bilayer. Instead, the peptide behavior is more consistent with that seen for the bilayer containing only unsaturated lipids, which is supported by lipid-specific interactions revealed by the simulations.
Published: 13 February 2023
Biophysica, Volume 3, pp 109-120; https://doi.org/10.3390/biophysica3010008
We used laser trapping to study the effects of suffruticosol B on lung cancer cells. Physical and mechanical changes were found to be statistically significant, with a 63.97% increase over untreated cells and a 79.57% increase over untreated cells after treatment for 3 or 6 h, respectively. The treatment affected the internal structure of the cells, with changes in their elastic properties. The cellular responses showed that treatment with suffruticosol B resulted in the decreased proliferation and invasion of cancer cells. These results suggest that the treatment may be useful in preventing or treating lung cancer.
Published: 8 February 2023
Biophysica, Volume 3, pp 93-108; https://doi.org/10.3390/biophysica3010007
Chromatins are structural components of chromosomes and consist of DNA and histone proteins. The structure, dynamics, and function of chromatins are important in regulating genetic processes. Several different experimental and theoretical tools have been employed to understand chromatins better. In this review, we will focus on the literatures engrossed in understanding of chromatins using single-molecule Förster resonance energy transfer (smFRET). smFRET is a single-molecule fluorescence microscopic technique that can furnish information regarding the distance between two points in space. This has been utilized to efficiently unveil the structural details of chromatins.
Published: 1 February 2023
Biophysica, Volume 3, pp 71-92; https://doi.org/10.3390/biophysica3010006
Flaviviruses are among the most critical pathogens in tropical regions; they cause various severe diseases in developing countries but are not restricted to these countries. The development of antiviral therapeutics is crucial for managing flavivirus outbreaks. Ten proteins are encoded in the flavivirus RNA. The N2B–NS3pro protein complex plays a fundamental role in flavivirus replication and is a promising drug target; however, no flavivirus protease inhibitors have progressed to the preclinical stage. This study analyzed the structural models and plasticity of the NS2B–NS3pro protein complex of five medically important non-dengue flaviviruses (West Nile, Rocio, Ilhéus, yellow fever, and Saint Louis encephalitis). The flavonoids amentoflavone, tetrahydrorobustaflavone, and quercetin were selected for their exceptional binding energies as potential inhibitors of the NS2B–NS3pro protein complex. AutoDock Vina results ranged from −7.0 kcal/mol to −11.5 kcal/mol and the compounds preferentially acted non-competitively. Additionally, the first structural model for the NS2B–NS3pro protein complex was proposed for Ilhéus and Rocio viruses. The NS2B–NS3pro protease is an attractive molecular target for drug development. The three identified natural flavonoids showed great inhibitory potential against the viral species. Nevertheless, further in silico and in vitro studies are required to obtain more information regarding NS2B–NS3pro inhibition by these flavonoids and their therapeutic potential.
Published: 28 January 2023
Biophysica, Volume 3, pp 69-70; https://doi.org/10.3390/biophysica3010005
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