Coarse-grained Molecular Dynamics Approach Research Articles

How antimicrobial peptide indolicidin and its derivatives interact with phospholipid membranes: Molecular dynamics simulation

Infections by drug-resistant bacteria pose a growing threat to human health, so developing new antimicrobial drugs is becoming an increasingly urgent requirement. Antimicrobial peptides are an important part of the innate immune system of many organisms, which have a broad spectrum of antimicrobial activity and little likelihood to trigger resistance, so they are considered good candidates for developing new antimicrobial drugs. In this paper, the interaction of indolicidin (IR13) and its derived peptides CP10A, CP-11 and cycloCP-11 with Gram-negative bacterial model membranes is investigated using coarse-grained molecular dynamics approach. The aim is to analyse the behaviour of these antimicrobial peptides when interacting with Gram-negative bacterial membranes. The widely studied phospholipid bilayer consisting of POPC and POPG is used as a Gram-negative bacterial membrane model in the simulations. The results show that the derived peptides CP-11 and cycloCP-11 are more active against Gram-negative bacteria than IR13 and CP10A. The dynamic behaviour of the four antimicrobial peptides on the membrane is different, and the peptide-membrane interactions induce changes in the thickness and surface area of the phospholipid bilayer, diminish membrane mobility, and so on. The present study provides important insights into the mechanism of interaction between antimicrobial peptides and phospholipid membranes by analysing them at the molecular level, and is therefore informative for designing new derivative peptides.

Deciphering the Cofilin Oligomers via Intermolecular Disulfide Bond Formation: A Coarse-Grained Molecular Dynamics Approach to Understanding Cofilin's Regulation on Actin Filaments.

Cofilin, a key actin-binding protein, orchestrates the dynamics of the actomyosin network through its actin-severing activity and by promoting the recycling of actin monomers. Recent experiments suggest that cofilin forms functionally distinct oligomers via thiol post-translational modifications (PTMs) that promote actin nucleation and assembly. Despite these advances, the structural conformations of cofilin oligomers that modulate actin activity remain elusive because there are combinatorial ways to oxidize thiols in cysteines to form disulfide bonds rapidly. This study employs molecular dynamics simulations to investigate human cofilin 1 as a case study for exploring cofilin dimers via disulfide bond formation. Utilizing a biasing scheme in simulations, we focus on analyzing dimer conformations conducive to disulfide bond formation. Additionally, we explore potential PTMs arising from the examined conformational ensemble. Using the free energy profiling, our simulations unveil a range of probable cofilin dimer structures not represented in current Protein Data Bank entries. These candidate dimers are characterized by their distinct population distributions and relative free energies. Of particular note is a dimer featuring an interface between cysteines 139 and 147 residues, which demonstrates stable free energy characteristics and intriguingly symmetrical geometry. In contrast, the experimentally proposed dimer structure exhibits a less stable free energy profile. We also evaluate frustration quantification based on the energy landscape theory in the protein-protein interactions at the dimer interfaces. Notably, the 39-39 dimer configuration emerges as a promising candidate for forming cofilin tetramers, as substantiated by frustration analysis. Additionally, docking simulations with actin filaments further evaluate the stability of these cofilin dimer-actin complexes. Our findings thus offer a computational framework for understanding the role of thiol PTM of cofilin proteins in regulating oligomerization, and the subsequent cofilin-mediated actin dynamics in the actomyosin network.

Effect of GM1 concentration change on plasma membrane: molecular dynamics simulation and analysis.

Ganglioside GM1 is a class of glycolipids predominantly located in the nervous system. Comprising a ceramide anchor and an oligosaccharide chain containing sialic acid, GM1 plays a pivotal role in various cellular processes, including signal transduction, cell adhesion, and membrane organization. Moreover, GM1 has been implicated in the pathogenesis of several neurological disorders, such as Parkinson's disease, Alzheimer's disease, and stroke. In this study, by creating a neural cell model membrane simulation system and employing rigorous molecular models, we utilize a coarse-grained molecular dynamics approach to explore the structural and dynamic characteristics of multi-component neuronal plasma membranes at varying GM1 ganglioside concentrations. The simulation results reveal that as GM1 concentration increases, a greater number of hydrogen bonds form between GM1 molecules, resulting in the formation of larger clusters, which leads to reduced membrane fluidity, increased lipid ordering, decreased membrane thickness and surface area and higher levels of GM1 dissociation. Through a meticulous analysis, while considering GM1's structural attributes, we offer valuable insights into the structural and dynamic traits of the cell membrane. This study provides a robust methodology for exploring membrane characteristics and enhances our comprehension of GM1 molecules, serving as a resource for both experimental and computational researchers in this field.

Nanoparticle-induced biomembrane fusion: unraveling the effect of core size on stalk formation.

Membrane fusion in vitro is a strategy to load model or cell-derived vesicles with proteins, drugs, and genetic materials for theranostic applications. It is thus crucial to develop strategies to control the fusion process, also through synthetic fusogenic agents. Ligand-protected, membrane-penetrating gold nanoparticles (Au NPs) can facilitate membrane fusion, but the molecular mechanisms remain unresolved. Here, we tackle NP-induced stalk formation using a coarse-grained molecular dynamics approach and enhanced sampling techniques. We show that smaller (2 nm in diameter) NPs lead to a lower free energy barrier and higher stalk stability than larger NPs (4 nm). We demonstrate that this difference is due to a different ligand conformational freedom, which in turn depends on the Au core curvature. Our study provides precious insights into the mechanisms underlying NP-mediated membrane fusion, while our computational approach is general and applicable to studying stalk formation caused by other fusogenic agents.

Water effect in the reverse micellar formation of docusate sodium. A coarse-grained molecular dynamics approach

Improving understanding and characterization of complex fluid systems are crucial tasks of integral product and process design. Of particular interest is the development of enhanced surfactants for industrial and household applications. In this work, a coarse-grained molecular model is developed to study docusate sodium-water-cyclohexane microemulsion systems. Most of the model parameters are taken from a corresponding states treatment of the statistical associating fluid theory-γ-Mie equation of state, overcoming time-consuming simulations. A good agreement is found between model predictions and experimental data, including the phase boundary and reverse micellar aggregation numbers. The effect of water over the morphology of single reverse micelles was studied over the water:surfactant molar ratio range 1 – 14, where a predominant spherical shape was obtained with an average shape anisotropy value of 0.003. The gained molecular insights would be further exploited for the design of more efficient, effective and non-toxic surfactants.

Simulation of magneto-mechanical response of ferrogel samples with various polymer structure

ABSTRACT Following the coarse-grained molecular dynamics approach, we propose a model of a small ferrogel sample (containing up to 1000 magnetic nanoparticles), in which the polymer matrix is presented in the form of a quasi-regular mesh of spring-beads chains and the filler particles are located at the mesh nodes. The state of the sample in the absence of an external field and in the process of quasi-static magnetization is considered for two types of mesh topology (simple cubic and diamond-like), different values of the filler concentration, the strength of dipole interaction, and the energy of magnetic anisotropy. Simulation shows that the use of a softer matrix with a diamond-like structure increases the magneto-mechanical response of the ferrogel. The presence of magnetic anisotropy leads to effective hardening of the ferrogel and, thus, prevents particle clustering and sample magnetization. It was also found that the anisotropy energy determines the type of field-induced changes in the sample volume – this aspect of material behavior is important for the use of ferrogels in controlled delivery and/or release of drugs.

Role of carbon nanotube in reinforcing cementitious materials: An experimental and coarse-grained molecular dynamics study

One-dimensional carbon-based nanomaterials, such as carbon nanotube (CNT) or carbon nanofiber (CNF) have been regarded as ideal candidates to form nanocomposites for the fabrication of high-performance cementitious materials. Although CNT, CNF and nanocellulose possess different mechanical properties, the mechanical enhancement of CNT, CNF or nanocellulose reinforced cementitious falls in a similar magnitude compared with plain cement paste, which should be highly related to the interaction between the nanomaterials and cement hydration products. In this study, CNT has been chosen as a representative nanomaterial to investigate the role in reinforcing cementitious materials in the nanocomposite system through an experimental and coarse-grained molecular dynamics approach. The findings suggest that the CNT changes the fracture process in cement matrix when the microcracks initiate with the significantly improved fracture energy, leading to the improved global mechanical properties, and a nanoscale interfacial transition zone is found that governs the failure of the nanocomposite system.

Unraveling the NaCl Concentration Effect on the First Stages of α-Synuclein Aggregation.

Intraneuronal aggregation of the intrinsically disordered protein α-synuclein is at the core of Parkinson's disease and related neurodegenerative disorders. Several reports show that the concentration of salts in the medium heavily affects its aggregation rate and fibril morphology, but a characterization of the individual monomeric conformations underlying these effects is still lacking. In this work, we have applied our α-synuclein-optimized coarse-grained molecular dynamics approach to decipher the structural features of the protein monomer under a range of NaCl concentrations (0.0-1.0 M). The results show that key intramolecular contacts between the terminal domains are lost at intermediate concentrations (leading to extended conformations likely to fibrillate), but recovered at high concentrations (leading to compact conformations likely to evolve toward amorphous aggregates). The pattern of direct interactions of the terminal α-synuclein domains with Na+ and Cl- ions plays a key role in explaining this effect. Our results are consistent with a recent study reporting a fibrillation enhancement at moderate NaCl concentrations but an inhibition at higher concentrations. The present work will contribute to improving our understanding of the structural features of monomeric α-synuclein, determining its NaCl-induced fibrillation propensity and the molecular basis of synucleinopathies, necessary for the future development of disease-halting therapies.

Oxidation degree of a cell membrane model and its response to structural changes, a coarse-grained molecular dynamics approach

Oxidative stress plays an essential role in the regulation of vital processes in living organisms. Reactive oxygen species can react chemically with the constituents of the cells leading to irreversible damage. The first structure of the cell in contact with the environment that surrounds it is the membrane, which protects it and allows the exchange of substances. Some signals manifest when the components of a bilayer are undergoing oxidation, like an increase in the lipid area, decrease in the thickness of the bilayer, and exchange of the oxidized groups toward the bilayer surface. In this investigation, a molecular dynamics simulation was done on a set of Dioleoylphosphatidylcholine membranes with different percentage of oxidized lipids, in order to observe the effect of the oxidation degree on the membrane structure. It was found that, as higher the concentration of oxidized lipids is, the larger the damage of the membrane. This is reflected in the increase in the lipid area and the decrease in the thickness and membrane packing. Also, it was observed that hydrophobicity inside the membrane decreases as the oxidation percentage increases. Communicated by Ramaswamy H. Sarma

Thermodynamic Investigation of the Mechanism of Heat Production During Membrane Depolarization.

When an action potential passes through a neuron, heat is first produced and then reabsorbed by the neuronal membrane, resulting in a small measurable temperature spike. Here, we describe the thermodynamics and molecular features of the heat production using a coarse-grained molecular dynamics approach. We study a simple unicomponent lipid bilayer membrane surrounded by physiological salt solution with and without an external electric field, which represents an imbalanced charge across the membrane. We show that the temperature increases significantly upon removal of the electric field under constant pressure conditions. The potential energy converted to heat is initially stored mainly in the imbalanced ion distribution across the membrane and the elastic energy of the membrane has only a minor role to play. We demonstrate that the mechanism of heat production involves interaction between ions as well as lipid headgroup dipoles while the interactions between polar water molecules and lipid headgroup dipoles absorbs a considerable portion of such produced heat upon removal of the electric field. Our data provide novel thermodynamic insights into the molecular processes governing membrane reorganization upon discharging of lipid membranes and insight into energy metabolism in nerves.

Buckling instability of smectic lamellar phase affected by the constituent molecular shape

Buckling instabilities and their collapse are major issues for the lamellar materials, and its mechanism at the molecular scale has not been fully addressed. We study the evolution of the lamellar structure under the lateral compression through the coarse-grained molecular dynamics approach. We investigate the influence of the molecular shape on their collapse based on explicit representation, and find that the critical strain of their collapse depends on the molecular shape. When the molecular length is smaller than the tip width of the chevron-like collective structure, the directors can be aligned in two possible directions parallel and perpendicular to the layers. This variation of molecular orientation causes the generation of isotropic domain wall. On the other hand, when the length of the molecules is longer than the tip width, the parallel misalignment is suppressed and the lamellar structure is more stable. Therefore, the ratio of the molecular length to the tip width affects the buckling instability of the lamellar structures.

Rotational Diffusion of Proteins in Nanochannels

The rotational diffusion coefficient is an essential parameter in determining the mechanistic features of biomolecules in both crowded and confined environments. Understanding the influence of nanoconfinement on rotational diffusion is vital in conceptualizing dynamics of biomolecules (such as proteins) in nanopores. The control of the translational movement of biomolecules is practiced widely in nanopore experiments. However, the restrictions on the translational movement may affect other dynamic properties such as rotational diffusion. In this paper, we use a coarse-grained molecular dynamics approach to study the rotational dynamics of a sample protein under the influence of cylindrical nanopore confinement. Our simulation reveals a 2-fold reduction in magnitude from the bulk rotational diffusion coefficient value as the confinement radius reaches double the size of protein's hydrodynamic radius. However, the changes in the rotational diffusion coefficient are relatively small compared to the changes in the translational diffusion coefficient. Interestingly, the rotational anisotropy also varies considerably when pore radii approach protein dimensions. Our simulations point out that the confinement effects cause the breakdown of small angular displacement theory when the pore radius is close to the protein hydrodynamic radius.

A Coarse-Grained Molecular Dynamics Approach to the Study of the Intrinsically Disordered Protein α-Synuclein.

Intrinsically disordered proteins (IDPs) are not well described by a single 3D conformation but by an ensemble of them, which makes their structural characterization especially challenging, both experimentally and computationally. Most all-atom force fields are designed for folded proteins and give too compact IDP conformations. α-Synuclein is a well-known IDP because of its relation to Parkinson's disease (PD). To understand its role in this disease at the molecular level, an efficient methodology is needed for the generation of conformational ensembles that are consistent with its known properties (in particular, with its dimensions) and that is readily extensible to post-translationally modified forms of the protein, commonly found in PD patients. Herein, we have contributed to this goal by performing explicit-solvent, microsecond-long Replica Exchange with Solute Scaling (REST2) simulations of α-synuclein with the coarse-grained force field SIRAH, finding that a 30% increase in the default strength of protein-water interactions yields a much better reproduction of its radius of gyration. Other known properties of α-synuclein, such as chemical shifts, secondary structure content, and long-range contacts, are also reproduced. Furthermore, we have simulated a glycated form of α-synuclein to suggest the extensibility of the method to its post-translationally modified forms. The computationally efficient REST2 methodology in combination with coarse-grained representations will facilitate the simulations of this relevant IDP and its modified forms, enabling a better understanding of their roles in disease and potentially leading to efficient therapies.

Molecular origins of elastoplastic behavior of polycarbonate under tension: A coarse-grained molecular dynamics approach

Polycarbonate (PC) is an important engineering polymer that has been used as the structural material in a wide range of applications. Using coarse-grained (CG) molecular dynamics (MD), this work systematically investigates the elastoplastic deformation of PC under two tension scenarios. To drastically improve computational efficiency, a new CG force field is developed for PC based on full-atom MD simulations. Effectiveness of the force field is verified by the calculations of glass transition temperature, Young’s modulus, strength, and distribution functions of bond stretching, bending and torsion. Using the newly developed force field, PC is found to undergo elastic deformation followed by the onset of yielding and plastic flow, in both uniaxial tension and constrained tension. The onset of yielding and plastic deformation are correlated with structural evolution using MD snapshots. Energy variations associated with bond stretching, bending and torsion are further analyzed to provide insights into their respective contributions to the deformation process. MD results are further compared with Argon’s model, which does not only accurately predict the mechanical strength of PC, but also provides molecular-level insights into the deformation mechanisms.

Design of pH-responsive “on-off” emulsions using CTAB/PPA emulsifiers by simulations and experiments

The pH-induced demulsification behaviors of “on-off” oil-in-water emulsions using cetyltrimethylammonium bromide (CTAB) and potassium phthalic acid (PPA) mixtures as emulsifiers were investigated by coarse-grained (CG) molecular dynamics (MD) simulations and experiments, aiming to design a new pH-responsive emulsion. On the one hand, we simulated the stability of emulsions of n-octane and aqueous CTAB/PPA solution, and phase diagrams of emulsion with different CTAB/PPA contents were observed at different pH. Furthermore, the demulsification processes from the low pH to high pH was investagated and clearly it began with film rupture and then accomplished with droplets fusion in few nanoseconds. Via analyzing the structure and molecular arrangment of the emulsion droplets, it was found that the reasons on pH-induced demulsification were weak hindrance effect of the surfactant film and electrostatic repulsion among emulsion droplets at high pH. On the other hand, through our experiments, the differences on stability of emulsions were verified and the reversible emulsification and demulsification processes by changing pH values were observed, which agreed well with our simulations. This work designed a new kind of pH-responsive emulsion using commercial surfactants CTAB/PPA by simulations and verified its pH-induced demulsification by experiments. It sets up a bridge between CG MD approach and experiment, which is expected to trigger further understanding and studies on stimuli responsive emulsion systems.

Understanding the Interfacial Mechanical Response of Nanoscale Polymer Thin Films via Nanoindentation

Understanding the mechanical properties of interphase regions in supported polymer thin films is critical as it yields key insights into the constitutive behavior of nanostructured materials. While studies have consistently shown that polymer layers near the substrate exhibit a stiffened response, the size of this region has been reported to vary based on the measurement approach, ranging from hundreds of nanometers in atomic force microscopy (AFM) nanoindentation experiments to a few nanometers in molecular simulations and thin film wrinkling experiments. Here we employ nanoindentation simulations using a coarse-grained molecular dynamics approach to investigate the elastic moduli gradients near the substrate interface of a supported poly(methyl methacrylate) (PMMA) thin film. We find that indenter sizes commonly used in experiments give rise to observed interphase length scales that are larger than the regions in which polymer dynamics are significantly altered as quantified by the segmental molecular s...

Interactions of Bio-Inspired Membranes with Peptides and Peptide-Mimetic Nanoparticles

Via Dissipative Particle Dynamics (DPD) and implicit solvent coarse-grained (CG) Molecular Dynamics (MD) we examine the interaction of an amphiphilic cell-penetrating peptide PMLKE and its synthetic counterpart with a bio-inspired membrane. We use the DPD technique to investigate the interaction of peptide-mimetic nanoparticles, or nanopins, with a three-component membrane. The CG MD approach is used to investigate the interaction of a cell-penetrating peptide PMLKE with single-component membrane. We observe the spontaneous binding and subsequent insertion of peptide and nanopin in the membrane by using CG MD and DPD approaches, respectively. In addition, we find that the insertion of peptide and nanopins is mainly driven by the favorable enthalpic interactions between the hydrophobic components of the peptide, or nanopin, and the membrane. Our study provides insights into the mechanism underlying the interactions of amphiphilic peptide and peptide-mimetic nanoparticles with a membrane. The result of this study can be used to guide the functional integration of peptide and peptide-mimetic nanoparticles with a cell membrane.

Buckling induced delamination of graphene composites through hybrid molecular modeling

The efficiency of graphene-based composites relies on mechanical stability and cooperativity, whereby separation of layers (i.e., delamination) can severely hinder performance. Here we study buckling induced delamination of mono- and bilayer graphene-based composites, utilizing a hybrid full atomistic and coarse-grained molecular dynamics approach. The coarse-grain model allows exploration of an idealized model material to facilitate parametric variation beyond any particular molecular structure. Through theoretical and simulation analyses, we show a critical delamination condition, where ΔD∝kL4, where ΔD is the change in bending stiffness (eV), k the stiffness of adhesion (eV/Å4), and L the length of the adhered section (Å).

Probing the structure of PEGylated-lipid assemblies by coarse-grained molecular dynamics

Poly(ethylene glycol) (PEG) and various zwitterionic species are now used routinely as components in soft biomaterials. The study of mixtures composed of PEGylated-lipids with zwitterionic lipids provides an excellent opportunity to understand molecular interactions in such systems. To this end, we examine the liposome/bicelle/micelle phase behavior of such mixtures in bulk solution and as monolayers at the air–water interface, utilizing a coarse-grained molecular-dynamics (CG-MD) approach rooted in experimental parameters that inform the nature of the short-range interactions. Specifically, we examine mixtures of PEGylated lipid and dimyristoylphosphatidylcholine (DMPC) lipid monolayers and find the standard force fields yield calculated surface tensions in agreement with experiment. Long-time CG-MD simulations (∼0.5 microsecond) of the self-assembly for different concentrations of PEG indicate the critical micellar size for the aggregate to form a bicelle from a spherical micellar nucleus. At lower PEG concentrations we find self-assembly of the PEGylated lipid into a liposome coexisting with a mixture of smaller bicelles. Examination of large individual bicelles (1000 lipids) at increasing concentrations of PEG indicates that the degree of PEG de-mixing towards the outer radius of the bicelle is correlated with the overall concentration of PEG in the bicelle. The CG-MD approach used herein should be a useful complement to experimental studies designed to probe solute (drug) interactions with such membrane systems.

Dynamics of micelle–nanoparticle systems undergoing shear: a coarse-grained molecular dynamics approach

Recent work has shown that polymeric micelles can template nanoparticles via interstitial sites in shear-ordered micelle solutions. In this work, we report results based on a coarse-grained molecular dynamics (CGMD) model of a solvent/polymer/nanoparticle system. Our results demonstrate the importance of polymer concentration and the micelle corona length in 2D shear-ordering of neat polymer solutions. Although our results do not show strong 3D ordering during shear, we find that cessation of shear allows the system to relax into a 3D configuration of greater order than without shear. It is further shown that this post-shear relaxation is strongly dependent on the length of the micelle corona. For the first time, we demonstrate the presence and importance of a flow disturbance surrounding micelles in simple shear flow at moderate Peclet numbers. This disturbance is similar to what is observed around simulated star polymers and ellipsoids. The extent of the flow disturbance increases as expected with a longer micelle corona length. It is further suggested that without proper consideration of these dynamics, a stable nanoparticle configuration would be difficult to obtain.