Editorial

4 pages, 198 KiB

Open AccessEditorial

Modeling and Simulation of Lipid Membranes

by Jordi Martí and Carles Calero

Membranes 2022, 12(6), 549; https://doi.org/10.3390/membranes12060549 - 25 May 2022

Cited by 1 | Viewed by 1645

Cell membranes separate the interior of cells and the exterior environment, providing protection, controlling the passage of substances, and governing the interaction with other biomolecules and signalling processes [...] Full article

(This article belongs to the Special Issue Modeling and Simulation of Lipid Membranes)

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17 pages, 6898 KiB

Open AccessArticle

Investigating Structural Dynamics of KCNE3 in Different Membrane Environments Using Molecular Dynamics Simulations

by Isaac K. Asare, Alberto Perez Galende, Andres Bastidas Garcia, Mateo Fernandez Cruz, Anna Clara Miranda Moura, Conner C. Campbell, Matthew Scheyer, John Paul Alao, Steve Alston, Andrea N. Kravats, Charles R. Sanders, Gary A. Lorigan and Indra D. Sahu

Membranes 2022, 12(5), 469; https://doi.org/10.3390/membranes12050469 - 27 Apr 2022

Cited by 3 | Viewed by 2083

Abstract

KCNE3 is a potassium channel accessory transmembrane protein that regulates the function of various voltage-gated potassium channels such as KCNQ1. KCNE3 plays an important role in the recycling of potassium ion by binding with KCNQ1. KCNE3 can be found in the small intestine, [...] Read more.

KCNE3 is a potassium channel accessory transmembrane protein that regulates the function of various voltage-gated potassium channels such as KCNQ1. KCNE3 plays an important role in the recycling of potassium ion by binding with KCNQ1. KCNE3 can be found in the small intestine, colon, and in the human heart. Despite its biological significance, there is little information on the structural dynamics of KCNE3 in native-like membrane environments. Molecular dynamics (MD) simulations are a widely used as a tool to study the conformational dynamics and interactions of proteins with lipid membranes. In this study, we have utilized all-atom molecular dynamics simulations to characterize the molecular motions and the interactions of KCNE3 in a bilayer composed of: a mixture of POPC and POPG lipids (3:1), POPC alone, and DMPC alone. Our MD simulation results suggested that the transmembrane domain (TMD) of KCNE3 is less flexible and more stable when compared to the N- and C-termini of KCNE3 in all three membrane environments. The conformational flexibility of N- and C-termini varies across these three lipid environments. The MD simulation results further suggested that the TMD of KCNE3 spans the membrane width, having residue A69 close to the center of the lipid bilayers and residues S57 and S82 close to the lipid bilayer membrane surfaces. These results are consistent with previous biophysical studies of KCNE3. The outcomes of these MD simulations will help design biophysical experiments and complement the experimental data obtained on KCNE3 to obtain a more detailed understanding of its structural dynamics in the native membrane environment. Full article

(This article belongs to the Special Issue Modeling and Simulation of Lipid Membranes)

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17 pages, 1656 KiB

Open AccessArticle

In Silico Drug Design of Benzothiadiazine Derivatives Interacting with Phospholipid Cell Membranes

by Zheyao Hu and Jordi Marti

Membranes 2022, 12(3), 331; https://doi.org/10.3390/membranes12030331 - 17 Mar 2022

Cited by 6 | Viewed by 2080

Abstract

The use of drugs derived from benzothiadiazine, a bicyclic heterocyclic benzene derivative, has become a widespread treatment for diseases such as hypertension, low blood sugar or the human immunodeficiency virus, among others. In this work we have investigated the interactions of benzothiadiazine and [...] Read more.

The use of drugs derived from benzothiadiazine, a bicyclic heterocyclic benzene derivative, has become a widespread treatment for diseases such as hypertension, low blood sugar or the human immunodeficiency virus, among others. In this work we have investigated the interactions of benzothiadiazine and four of its derivatives designed in silico with model zwitterionic cell membranes formed by dioleoylphosphatidylcholine, 1,2-dioleoyl-sn-glycero-3-phosphoserine and cholesterol at the liquid–crystal phase inside aqueous potassium chloride solution. We have elucidated the local structure of benzothiadiazine by means of microsecond molecular dynamics simulations of systems including a benzothiadiazine molecule or one of its derivatives. Such derivatives were obtained by the substitution of a single hydrogen site of benzothiadiazine by two different classes of chemical groups, one of them electron-donating groups (methyl and ethyl) and another one by electron-accepting groups (fluorine and trifluoromethyl). Our data have revealed that benzothiadiazine derivatives have a strong affinity to stay at the cell membrane interface although their solvation characteristics can vary significantly—they can be fully solvated by water in short periods of time or continuously attached to specific lipid sites during intervals of 10–70 ns. Furthermore, benzothiadiazines are able to bind lipids and cholesterol chains by means of single and double hydrogen-bonds of characteristic lengths between 1.6 and 2.1 Å. Full article

(This article belongs to the Special Issue Modeling and Simulation of Lipid Membranes)

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27 pages, 4492 KiB

Open AccessArticle

Microfluidics Approach to the Mechanical Properties of Red Blood Cell Membrane and Their Effect on Blood Rheology

by Claudia Trejo-Soto, Guillermo R. Lázaro, Ignacio Pagonabarraga and Aurora Hernández-Machado

Membranes 2022, 12(2), 217; https://doi.org/10.3390/membranes12020217 - 13 Feb 2022

Cited by 18 | Viewed by 4443

Abstract

In this article, we describe the general features of red blood cell membranes and their effect on blood flow and blood rheology. We first present a basic description of membranes and move forward to red blood cell membranes’ characteristics and modeling. We later [...] Read more.

In this article, we describe the general features of red blood cell membranes and their effect on blood flow and blood rheology. We first present a basic description of membranes and move forward to red blood cell membranes’ characteristics and modeling. We later review the specific properties of red blood cells, presenting recent numerical and experimental microfluidics studies that elucidate the effect of the elastic properties of the red blood cell membrane on blood flow and hemorheology. Finally, we describe specific hemorheological pathologies directly related to the mechanical properties of red blood cells and their effect on microcirculation, reviewing microfluidic applications for the diagnosis and treatment of these diseases. Full article

(This article belongs to the Special Issue Modeling and Simulation of Lipid Membranes)

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16 pages, 3304 KiB

Open AccessEditor’s ChoiceArticle

Phosphatidylserine Exposed Lipid Bilayer Models for Understanding Cancer Cell Selectivity of Natural Compounds: A Molecular Dynamics Simulation Study

by Navaneethan Radhakrishnan, Sunil C. Kaul, Renu Wadhwa and Durai Sundar

Membranes 2022, 12(1), 64; https://doi.org/10.3390/membranes12010064 - 01 Jan 2022

Cited by 6 | Viewed by 4152

Abstract

Development of drugs that are selectively toxic to cancer cells and safe to normal cells is crucial in cancer treatment. Evaluation of membrane permeability is a key metric for successful drug development. In this study, we have used in silico molecular models of [...] Read more.

Development of drugs that are selectively toxic to cancer cells and safe to normal cells is crucial in cancer treatment. Evaluation of membrane permeability is a key metric for successful drug development. In this study, we have used in silico molecular models of lipid bilayers to explore the effect of phosphatidylserine (PS) exposure in cancer cells on membrane permeation of natural compounds Withaferin A (Wi-A), Withanone (Wi-N), Caffeic Acid Phenethyl Ester (CAPE) and Artepillin C (ARC). Molecular dynamics simulations were performed to compute permeability coefficients. The results indicated that the exposure of PS in cancer cell membranes facilitated the permeation of Wi-A, Wi-N and CAPE through a cancer cell membrane when compared to a normal cell membrane. In the case of ARC, PS exposure did not have a notable influence on its permeability coefficient. The presented data demonstrated the potential of PS exposure-based models for studying cancer cell selectivity of drugs. Full article

(This article belongs to the Special Issue Modeling and Simulation of Lipid Membranes)

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28 pages, 2978 KiB

Open AccessArticle

Mutually Beneficial Combination of Molecular Dynamics Computer Simulations and Scattering Experiments

by Nebojša Zec, Gaetano Mangiapia, Alex C. Hendry, Robert Barker, Alexandros Koutsioubas, Henrich Frielinghaus, Mario Campana, José Luis Ortega-Roldan, Sebastian Busch and Jean-François Moulin

Membranes 2021, 11(7), 507; https://doi.org/10.3390/membranes11070507 - 05 Jul 2021

Cited by 5 | Viewed by 3701

Abstract

We showcase the combination of experimental neutron scattering data and molecular dynamics (MD) simulations for exemplary phospholipid membrane systems. Neutron and X-ray reflectometry and small-angle scattering measurements are determined by the scattering length density profile in real space, but it is not usually [...] Read more.

We showcase the combination of experimental neutron scattering data and molecular dynamics (MD) simulations for exemplary phospholipid membrane systems. Neutron and X-ray reflectometry and small-angle scattering measurements are determined by the scattering length density profile in real space, but it is not usually possible to retrieve this profile unambiguously from the data alone. MD simulations predict these density profiles, but they require experimental control. Both issues can be addressed simultaneously by cross-validating scattering data and MD results. The strengths and weaknesses of each technique are discussed in detail with the aim of optimizing the opportunities provided by this combination. Full article

(This article belongs to the Special Issue Modeling and Simulation of Lipid Membranes)

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14 pages, 2398 KiB

Open AccessArticle

A Study of the Interaction of a New Benzimidazole Schiff Base with Synthetic and Simulated Membrane Models of Bacterial and Mammalian Membranes

by Alberto Aragón-Muriel, Yamil Liscano, David Morales-Morales, Dorian Polo-Cerón and Jose Oñate-Garzón

Membranes 2021, 11(6), 449; https://doi.org/10.3390/membranes11060449 - 16 Jun 2021

Cited by 6 | Viewed by 3081

Abstract

Biological membranes are complex dynamic systems composed of a great variety of carbohydrates, lipids, and proteins, which together play a pivotal role in the protection of organisms and through which the interchange of different substances is regulated in the cell. Given the complexity [...] Read more.

Biological membranes are complex dynamic systems composed of a great variety of carbohydrates, lipids, and proteins, which together play a pivotal role in the protection of organisms and through which the interchange of different substances is regulated in the cell. Given the complexity of membranes, models mimicking them provide a convenient way to study and better understand their mechanisms of action and their interactions with biologically active compounds. Thus, in the present study, a new Schiff base (Bz-Im) derivative from 2-(m-aminophenyl)benzimidazole and 2,4-dihydroxybenzaldehyde was synthesized and characterized by spectroscopic and spectrometric techniques. Interaction studies of (Bz-Im) with two synthetic membrane models prepared with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and DMPC/1,2-dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG) 3:1 mixture, imitating eukaryotic and prokaryotic membranes, respectively, were performed by applying differential scanning calorimetry (DSC). Molecular dynamics simulations were also developed to better understand their interactions. In vitro and in silico assays provided approaches to understand the effect of Bz-Im on these lipid systems. The DSC results showed that, at low compound concentrations, the effects were similar in both membrane models. By increasing the concentration of Bz-Im, the DMPC/DMPG membrane exhibited greater fluidity as a result of the interaction with Bz-Im. On the other hand, molecular dynamics studies carried out on the erythrocyte membrane model using the phospholipids POPE (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine), SM (N-(15Z-tetracosenoyl)-sphing-4-enine-1-phosphocholine), and POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) revealed that after 30 ns of interaction, both hydrophobic interactions and hydrogen bonds were responsible for the affinity of Bz-Im for PE and SM. The interactions of the imine with POPG (1-Palmitoyl-2-Oleoyl-sn-Glycero-3-Phosphoglycerol) in the E. coli membrane model were mainly based on hydrophobic interactions. Full article

(This article belongs to the Special Issue Modeling and Simulation of Lipid Membranes)

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19 pages, 11634 KiB

Open AccessArticle

Influence of Cholesterol on the Orientation of the Farnesylated GTP-Bound KRas-4B Binding with Anionic Model Membranes

by Huixia Lu and Jordi Martí

Membranes 2020, 10(11), 364; https://doi.org/10.3390/membranes10110364 - 22 Nov 2020

Cited by 5 | Viewed by 2104

Abstract

The Ras family of proteins is tethered to the inner leaflet of the cell membranes which plays an essential role in signal transduction pathways that promote cellular proliferation, survival, growth, and differentiation. KRas-4B, the most mutated Ras isoform in different cancers, has been [...] Read more.

The Ras family of proteins is tethered to the inner leaflet of the cell membranes which plays an essential role in signal transduction pathways that promote cellular proliferation, survival, growth, and differentiation. KRas-4B, the most mutated Ras isoform in different cancers, has been under extensive study for more than two decades. Here we have focused our interest on the influence of cholesterol on the orientations that KRas-4B adopts with respect to the plane of the anionic model membranes. How cholesterol in the bilayer might modulate preferences for specific orientation states is far from clear. Herein, after analyzing data from in total 4000 ns-long molecular dynamics (MD) simulations for four KRas-4B systems, properties such as the area per lipid and thickness of the membrane as well as selected radial distribution functions, penetration of different moieties of KRas-4B, and internal conformational fluctuations of flexible moieties in KRas-4B have been calculated. It has been shown that high cholesterol content in the plasma membrane (PM) favors one orientation state (OS

_{1}

), exposing the effector-binding loop for signal transduction in the cell from the atomic level. We confirm that high cholesterol in the PM helps KRas-4B mutant stay in its constitutively active state, which suggests that high cholesterol intake can increase mortality and may promote cancer progression for cancer patients. We propose that during the treatment of KRas-4B-related cancers, reducing the cholesterol level in the PM and sustaining cancer progression by controlling the plasma cholesterol intake might be taken into account in anti-cancer therapies. Full article

(This article belongs to the Special Issue Modeling and Simulation of Lipid Membranes)

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15 pages, 8366 KiB

Open AccessArticle

Study of the Interaction of a Novel Semi-Synthetic Peptide with Model Lipid Membranes

by Lucia Sessa, Simona Concilio, Peter Walde, Tom Robinson, Petra S. Dittrich, Amalia Porta, Barbara Panunzi, Ugo Caruso and Stefano Piotto

Membranes 2020, 10(10), 294; https://doi.org/10.3390/membranes10100294 - 19 Oct 2020

Cited by 9 | Viewed by 2758

Abstract

Most linear peptides directly interact with membranes, but the mechanisms of interaction are far from being completely understood. Here, we present an investigation of the membrane interactions of a designed peptide containing a non-natural, synthetic amino acid. We selected a nonapeptide that is [...] Read more.

Most linear peptides directly interact with membranes, but the mechanisms of interaction are far from being completely understood. Here, we present an investigation of the membrane interactions of a designed peptide containing a non-natural, synthetic amino acid. We selected a nonapeptide that is reported to interact with phospholipid membranes, ALYLAIRKR, abbreviated as ALY. We designed a modified peptide (azoALY) by substituting the tyrosine residue of ALY with an antimicrobial azobenzene-bearing amino acid. Both of the peptides were examined for their ability to interact with model membranes, assessing the penetration of phospholipid monolayers, and leakage across the bilayer of large unilamellar vesicles (LUVs) and giant unilamellar vesicles (GUVs). The latter was performed in a microfluidic device in order to study the kinetics of leakage of entrapped calcein from the vesicles at the single vesicle level. Both types of vesicles were prepared from a 9:1 (mol/mol) mixture of POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) and POPG (1-palmitoyl-2-oleoyl-sn-glycero-3-phospho(1′-rac-glycerol). Calcein leakage from the vesicles was more pronounced at a low concentration in the case of azoALY than for ALY. Increased vesicle membrane disturbance in the presence of azoALY was also evident from an enzymatic assay with LUVs and entrapped horseradish peroxidase. Molecular dynamics simulations of ALY and azoALY in an anionic POPC/POPG model bilayer showed that ALY peptide only interacts with the lipid head groups. In contrast, azoALY penetrates the hydrophobic core of the bilayers causing a stronger membrane perturbation as compared to ALY, in qualitative agreement with the experimental results from the leakage assays. Full article

(This article belongs to the Special Issue Modeling and Simulation of Lipid Membranes)

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