Research

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19 pages, 3236 KiB

Open AccessArticle

Permeation of a Homologous Series of NBD-Labeled Fatty Amines through Lipid Bilayers: A Molecular Dynamics Study

by Hugo A. L. Filipe, Luís M. S. Loura and Maria João Moreno

Membranes 2023, 13(6), 551; https://doi.org/10.3390/membranes13060551 - 25 May 2023

Cited by 2 | Viewed by 1098

Permeation through biomembranes is ubiquitous for drugs to reach their active sites. Asymmetry of the cell plasma membrane (PM) has been described as having an important role in this process. Here we describe the interaction of a homologous series of 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD)-labeled amphiphiles [...] Read more.

Permeation through biomembranes is ubiquitous for drugs to reach their active sites. Asymmetry of the cell plasma membrane (PM) has been described as having an important role in this process. Here we describe the interaction of a homologous series of 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD)-labeled amphiphiles (NBD-Cn, n = 4 to 16) with lipid bilayers of different compositions (1-palmitoyl, 2-oleoyl-sn-glycero-3-phosphocholine (POPC):cholesterol (1:1) and palmitoylated sphingomyelin (SpM):cholesterol (6:4)), including an asymmetric bilayer. Both unrestrained and umbrella sampling (US) simulations (at varying distances to the bilayer center) were carried out. The free energy profile of NBD-Cn at different depths in the membrane was obtained from the US simulations. The behavior of the amphiphiles during the permeation process was described regarding their orientation, chain elongation, and H-bonding to lipid and water molecules. Permeability coefficients were also calculated for the different amphiphiles of the series, using the inhomogeneous solubility-diffusion model (ISDM). Quantitative agreement with values obtained from kinetic modeling of the permeation process could not be obtained. However, for the longer, and more hydrophobic amphiphiles, the variation trend along the homologous series was qualitatively better matched by the ISDM when the equilibrium location of each amphiphile was taken as reference (ΔG = 0), compared to the usual choice of bulk water. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulations in Biological Membrane Systems)

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20 pages, 2336 KiB

Open AccessArticle

SARS-CoV-2 Protein S Fusion Peptide Is Capable of Wrapping Negatively-Charged Phospholipids

by José Villalaín

Membranes 2023, 13(3), 344; https://doi.org/10.3390/membranes13030344 - 16 Mar 2023

Cited by 3 | Viewed by 2228

Abstract

COVID-19, caused by SARS-CoV-2, which is a positive-sense, single-stranded RNA enveloped virus, emerged in late 2019 and was declared a worldwide pandemic in early 2020 causing more than 600 million infections so far and more than 6 million deaths in the world. Although [...] Read more.

COVID-19, caused by SARS-CoV-2, which is a positive-sense, single-stranded RNA enveloped virus, emerged in late 2019 and was declared a worldwide pandemic in early 2020 causing more than 600 million infections so far and more than 6 million deaths in the world. Although new vaccines have been implemented, the pandemic continues to impact world health dramatically. Membrane fusion, critical for the viral entry into the host cell, is one of the main targets for the development of novel antiviral therapies to combat COVID-19. The S2 subunit of the viral S protein, a class I membrane fusion protein, contains the fusion domain which is directly implicated in the fusion mechanism. The knowledge of the membrane fusion mechanism at the molecular level will undoubtedly result in the development of effective antiviral strategies. We have used all-atom molecular dynamics to analyse the binding of the SARS-CoV-2 fusion peptide to specific phospholipids in model membranes composed of only one phospholipid plus cholesterol in the presence of either Na⁺ or Ca²⁺. Our results show that the fusion peptide is capable of binding to the membrane, that its secondary structure does not change significantly upon binding, that it tends to preferentially bind electronegatively charged phospholipids, and that it does not bind cholesterol at all. Understanding the intricacies of the membrane fusion mechanism and the molecular interactions involved will lead us to the development of antiviral molecules that will allow a more efficient battle against these viruses. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulations in Biological Membrane Systems)

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18 pages, 7694 KiB

Open AccessArticle

The Effect of Cholesterol in SOPC Lipid Bilayers at Low Temperatures

by Nikoleta Ivanova and Hassan Chamati

Membranes 2023, 13(3), 275; https://doi.org/10.3390/membranes13030275 - 26 Feb 2023

Cited by 3 | Viewed by 1297

Abstract

We study the behavior of lipid bilayers composed of SOPC (1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine) with different concentrations of cholesterol, ranging from 10 mol% to 50 mol% at 273 K. To this end, we carry out extensive atomistic molecular dynamic simulations with the aid of the Slipid [...] Read more.

We study the behavior of lipid bilayers composed of SOPC (1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine) with different concentrations of cholesterol, ranging from 10 mol% to 50 mol% at 273 K. To this end, we carry out extensive atomistic molecular dynamic simulations with the aid of the Slipid force field aiming at computing basic bilayer parameters, as well as thermodynamic properties and structural characteristics. The obtained results are compared to available relevant experimental data and the outcome of atomistic simulations performed on bilayers composed of analogous phospholipids. Our results show a good quantitative, as well as qualitative, agreement with the main trends associated with the concentration increase in cholesterol. Moreover, it comes out that a change in the behavior of the bilayer is brought about at a concentration of about 30 mol% cholesterol. At this very concentration, some of the bilayer properties are found to exhibit a saturation and a significant long-range ordering of the lipid molecules in the membrane shows up. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulations in Biological Membrane Systems)

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12 pages, 35373 KiB

Open AccessArticle

Low-THz Vibrations of Biological Membranes

by Chloe Luyet, Paolo Elvati, Jordan Vinh and Angela Violi

Membranes 2023, 13(2), 139; https://doi.org/10.3390/membranes13020139 - 21 Jan 2023

Cited by 2 | Viewed by 1330

Abstract

A growing body of work has linked key biological activities to the mechanical properties of cellular membranes, and as a means of identification. Here, we present a computational approach to simulate and compare the vibrational spectra in the low-THz region for mammalian and [...] Read more.

A growing body of work has linked key biological activities to the mechanical properties of cellular membranes, and as a means of identification. Here, we present a computational approach to simulate and compare the vibrational spectra in the low-THz region for mammalian and bacterial membranes, investigating the effect of membrane asymmetry and composition, as well as the conserved frequencies of a specific cell. We find that asymmetry does not impact the vibrational spectra, and the impact of sterols depends on the mobility of the components of the membrane. We demonstrate that vibrational spectra can be used to distinguish between membranes and, therefore, could be used in identification of different organisms. The method presented, here, can be immediately extended to other biological structures (e.g., amyloid fibers, polysaccharides, and protein-ligand structures) in order to fingerprint and understand vibrations of numerous biologically-relevant nanoscale structures. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulations in Biological Membrane Systems)

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11 pages, 5843 KiB

Open AccessArticle

Effects of the RNA-Polymerase Inhibitors Remdesivir and Favipiravir on the Structure of Lipid Bilayers—An MD Study

by Mauro Bringas, Meike Luck, Peter Müller, Holger A. Scheidt and Santiago Di Lella

Membranes 2022, 12(10), 941; https://doi.org/10.3390/membranes12100941 - 27 Sep 2022

Viewed by 2208

Abstract

The structure and dynamics of membranes are crucial to ensure the proper functioning of cells. There are some compounds used in therapeutics that show nonspecific interactions with membranes in addition to their specific molecular target. Among them, two compounds recently used in therapeutics [...] Read more.

The structure and dynamics of membranes are crucial to ensure the proper functioning of cells. There are some compounds used in therapeutics that show nonspecific interactions with membranes in addition to their specific molecular target. Among them, two compounds recently used in therapeutics against COVID-19, remdesivir and favipiravir, were subjected to molecular dynamics simulation assays. In these, we demonstrated that the compounds can spontaneously bind to model lipid membranes in the presence or absence of cholesterol. These findings correlate with the corresponding experimental results recently reported by our group. In conclusion, insertion of the compounds into the membrane is observed, with a mean position close to the phospholipid head groups. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulations in Biological Membrane Systems)

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10 pages, 3810 KiB

Open AccessArticle

Molecular Dynamics Simulation of Transport Mechanism of Graphene Quantum Dots through Different Cell Membranes

by Pengzhen Zhang, Fangfang Jiao, Lingxiao Wu, Zhe Kong, Wei Hu, Lijun Liang and Yongjun Zhang

Membranes 2022, 12(8), 753; https://doi.org/10.3390/membranes12080753 - 31 Jul 2022

Cited by 1 | Viewed by 1809

Abstract

Exploring the mechanisms underlying the permeation of graphene quantum dots (GQDs) through different cell membranes is key for the practical application of GQDs in medicine. Here, the permeation process of GQDs through different lipid membranes was evaluated using molecular dynamics (MD) simulations. Our [...] Read more.

Exploring the mechanisms underlying the permeation of graphene quantum dots (GQDs) through different cell membranes is key for the practical application of GQDs in medicine. Here, the permeation process of GQDs through different lipid membranes was evaluated using molecular dynamics (MD) simulations. Our results showed that GQDs can easily permeate into 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) lipid membranes with low phospholipid molecule densities but cannot permeate into 1-palmitoyl-2-oleoyl phosphatidylethanolamine (POPE) lipid membranes with high phospholipid densities. Free energy calculation showed that a high-energy barrier exists on the surface of the POPE lipid membrane, which prevents GQDs from entering the cell membrane interior. Further analysis of the POPE membrane structure showed that sparsely arranged phospholipid molecules of the low-density lipid membrane facilitated the entry of GQDs into the interior of the membrane, compared to compactly arranged molecules in the high-density lipid membrane. Our simulation study provides new insights into the transmembrane transport of GQDs. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulations in Biological Membrane Systems)

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Review

Jump to: Research

14 pages, 4605 KiB

Open AccessReview

Recent Advances in Molecular Dynamics Simulations of Tau Fibrils and Oligomers

by Prechiel A. Barredo and Mannix P. Balanay

Membranes 2023, 13(3), 277; https://doi.org/10.3390/membranes13030277 - 26 Feb 2023

Cited by 1 | Viewed by 1905

Abstract

The study of tau protein aggregation and interactions with other molecules or solvents using molecular dynamics simulations (MDs) is of interest to many researchers to propose new mechanism-based therapeutics for neurodegenerative diseases such as Alzheimer’s disease, Pick’s disease, chronic traumatic encephalopathy, and other [...] Read more.

The study of tau protein aggregation and interactions with other molecules or solvents using molecular dynamics simulations (MDs) is of interest to many researchers to propose new mechanism-based therapeutics for neurodegenerative diseases such as Alzheimer’s disease, Pick’s disease, chronic traumatic encephalopathy, and other tauopathies. In this review, we present recent MD simulation studies of tau oligomers and fibrils such as tau-NPK, tau-PHF, tau-K18, and tau-R3-R4 monomers and dimers. All-atom simulations by replica exchange MDs and coarse-grained MDs in lipid bilayers and in solution were used. The simulations revealed different mechanisms in the binding of tau in bilayers and in solutions, depending on the peptide size. Phosphorylation is also an important factor in MD simulations. The use of steered MDs was also included to simulate the dissociation of tau fibrils. The exponential improvement in the computing power of computers has led to an increasing number of scientists and engineers using a cost-effective, high-performance computing platform to study how the tau protein interacts and the effects of changing its structure, such as the phosphorylation of tau fibrils. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulations in Biological Membrane Systems)

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32 pages, 4198 KiB

Open AccessReview

Current Trends and Changes in Use of Membrane Molecular Dynamics Simulations within Academia and the Pharmaceutical Industry

by Stephan L. Watkins

Membranes 2023, 13(2), 148; https://doi.org/10.3390/membranes13020148 - 24 Jan 2023

Cited by 1 | Viewed by 2901

Abstract

There has been an almost exponential increase in the use of molecular dynamics simulations in basic research and industry over the last 5 years, with almost a doubling in the number of publications each year. Many of these are focused on neurological membranes, [...] Read more.

There has been an almost exponential increase in the use of molecular dynamics simulations in basic research and industry over the last 5 years, with almost a doubling in the number of publications each year. Many of these are focused on neurological membranes, and biological membranes in general, applied to the medical industry. A smaller portion have utilized membrane simulations to answer more basic questions related to the function of specific proteins, chemicals or biological processes. This review covers some newer studies, alongside studies from the last two decades, to determine changes in the field. Some of these are basic, while others are more profound, such as multi-component embedded membrane machinery. It is clear that many facets of the discipline remain the same, while the focus on and uses of the technology are broadening in scope and utilization as a general research tool. Analysis of recent literature provides an overview of the current methodologies, covers some of the recent trends or advances and tries to make predictions of the overall path membrane molecular dynamics will follow in the coming years. In general, the overview presented is geared towards the general scientific community, who may wish to introduce the use of these methodologies in light of these changes, making molecular dynamic simulations more feasible for general scientific or medical research. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulations in Biological Membrane Systems)

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17 pages, 1934 KiB

Open AccessReview

Applications of Molecular Dynamics Simulation in Protein Study

by Siddharth Sinha, Benjamin Tam and San Ming Wang

Membranes 2022, 12(9), 844; https://doi.org/10.3390/membranes12090844 - 29 Aug 2022

Cited by 17 | Viewed by 4533

Abstract

Molecular Dynamics (MD) Simulations is increasingly used as a powerful tool to study protein structure-related questions. Starting from the early simulation study on the photoisomerization in rhodopsin in 1976, MD Simulations has been used to study protein function, protein stability, protein–protein interaction, enzymatic [...] Read more.

Molecular Dynamics (MD) Simulations is increasingly used as a powerful tool to study protein structure-related questions. Starting from the early simulation study on the photoisomerization in rhodopsin in 1976, MD Simulations has been used to study protein function, protein stability, protein–protein interaction, enzymatic reactions and drug–protein interactions, and membrane proteins. In this review, we provide a brief review for the history of MD Simulations application and the current status of MD Simulations applications in protein studies. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulations in Biological Membrane Systems)

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