Coarse grained MD simulation of bulk and interfacial behavior of mixture of CTAB/SDS surfactants.

CONTEXT: This study involves simulating the process of inhibiting corrosion through the formation of micelles by surfactants and their deposition on iron (Fe) surfaces. The primary focus is on examining CTAB/SDS mixtures in aqueous solutions with different concentrations. Micelle properties, including size, shape, aggregation number, cluster size, and surfactant diffusion, were calculated and validated with experimental data. The coarse-grained Fe surface was modeled and validated against experimental water contact-angle data. Subsequently, the deposition of CTAB/SDS mixtures on the Fe surface and air-water interface was studied systematically. We found that the relative ratio of CTAB/SDS in the solution directly influences surfactant deposition behavior, which might impact the corrosion inhibition efficiency. METHODS: All the MD simulations were performed using the GROMACS software with MARTINI2 force field and Martini polar water. The molecules are packed using PACKMOL software. Both NVT and NPT simulations are caried out at temperature and pressure of 303 K and 1 bar respectively, with a nonbonded interaction cut-off (rcut) of 1.1 nm. The LJ potential was shifted from 0.9 nm to rcut, while the electrostatic potential was shifted from 0.0 nm to rcut. For electrostatics, reaction-field coulomb type is used, relative dielectric constant (epsilon-r) and the reaction field dielectric constant (epsilon-rf) are equal to 2.5 and infinity respectively. The dielectric constant below rcut is epsilon-r, and beyond the cut-off is epsilon-rf. Coulomb-modifier used as potential-shift which leads to shift in the coulomb potential by a constant such that it is zero at the rcut. This makes the potential of the integral of the force . The neighbor list was updated every 10 steps, employing a neighbor list cut-off equal to rcut. Using a polar water model, we used a constant time step of 0.02 ps throughout the simulation. The used epsilon-r = 2.5, is recommended for polar water.

Elucidating collective translocation of nanoparticles across the skin lipid matrix: a molecular dynamics study.

The top layer of skin, the stratum corneum, provides a formidable barrier to the skin. Nanoparticles are utilized and further explored for personal and health care applications related to the skin. In the past few years, several researchers have studied the translocation and permeation of nanoparticles of various shapes, sizes, and surface chemistry through cell membranes. Most of these studies focused on a single nanoparticle and a simple bilayer system, whereas skin has a highly complex lipid membrane architecture. Moreover, it is highly unlikely that a nanoparticle formulation applied on the skin will not have multiple nanoparticle-nanoparticle and skin-nanoparticle interactions. In this study, we have utilized coarse-grained MARTINI molecular dynamics simulations to assess the interactions of two types (bare and dodecane-thiol coated) of nanoparticles with two models (single bilayer and double bilayer) of skin lipid membranes. The nanoparticles were found to be partitioned from the water layer to the lipid membrane as an individual entity as well as in the cluster form. It was discovered that each nanoparticle reached the interior of both single bilayer and double bilayer membranes irrespective of the nanoparticle type and concentration, though coated particles were observed to efficiently traverse across the bilayer when compared with bare particles. The coated nanoparticles also created a single large cluster inside the membrane, whereas the bare nanoparticles were found in small clusters. Both the nanoparticles exhibited preferential interactions with cholesterol molecules present in the lipid membrane as compared to other lipid components of the membrane. We have also observed that the single membrane model exhibited unrealistic instability at moderate to higher concentrations of nanoparticles, and hence for translocation study, a minimum double bilayer model should be employed.

Investigating the nanostructure of a CER[NP]/CER[AP]-based stratum corneum lipid matrix model: A combined neutron diffraction & molecular dynamics simulations approach.

The human skin provides a physiochemical and biological protective barrier due to the unique structure of its outermost layer known as the Stratum corneum. This layer consists of corneocytes and a multi-lamellar lipid matrix forming a composite, which is a major determining factor for the barrier function of the Stratum corneum. A substantiated understanding of this barrier is necessary, as controlled breaching or modulation of the same is also essential for various health and personal care applications such as topical drug delivery and cosmetics to a name few. In this study, we discuss the state-of-the-art of neutron diffraction techniques, using specifically deuterated lipids, combined with the information obtained from molecular models using molecular dynamics simulations, to understand the structure and barrier function of the Stratum corneum lipid matrix. As an example, the effect of ceramide concentration on a lipid lamella system consisting of CER[NP]/CER[AP]/Cholesterol/free fatty acid (deprotonated) is studied. This study demonstrates the usefulness of the combined approach of neutron diffraction and molecular dynamics simulations for effective analysis of the model systems created for the Stratum corneum lipid matrix. The optimization of force fields by comparison with experimental data is furthermore an important step in the direction of providing a predictive quality.

Peptide mediated colorimetric detection of SARS-CoV-2 using gold nanoparticles: a molecular dynamics simulation study.

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has necessitated the development of a rapid, simple yet selective naked-eye detection methodology that does not require any advanced instrumental techniques. In this study, we report our computational findings on the detection of SARS-CoV-2 using peptide- functionalized gold nanoparticles (GNPs). The peptide has been screened from angiotensin-converting enzyme 2 (ACE2) receptor situated on the surface of the host cell membrane which interacts with the spike protein of SARS-CoV-2, resulting entry of the virus into the host cell. As a result, the peptide-functionalized GNPs possess excellent affinity towards the spikes of SARS-CoV-2 and readily get aggregated once exposed to SARS-CoV-2 antigen or virus. The stability of the peptides on the surface of GNPs and their interaction with the spike protein of the virus have been investigated using coarse-grained molecular dynamic simulations. The potential of mean force calculation of spike protein confirmed strong binding between peptide and receptor-binding domain (RBD) of spike protein. Our in silico results demonstrate the potential of the peptide-functionalized GNPs in the development of simple and rapid colorimetric biosensors for clinical diagnosis.

Development and characterization of stabilized omega-3 fatty acid and micronutrient emulsion formulation for food fortification.

We report a novel stabilized emulsified formulation containing omega-3 fatty acid (ω-3 FA) and micronutrient that can be readily used for food fortification. The emulsification methodology for producing a stabilized formulation containing both ω-3 FA and micronutrients is described. The formulation was developed considering the human requirement of ω-3 FA and recommended daily allowance of important micronutrients. This formulation was characterized for physical appearance, pH, specific gravity, color measurement etc. Fatty acid analysis revealed formulations (2, 4 and 5 g/serve) were able to provide 500-1300 mg of alpha linoleic acid. Oxidative stability assessment (peroxide value, free fatty acid content) of the formulations showed, stability of the formulation as non-significant alterations were noted in these parameters when the formulations were compared with raw flaxseed oil. Rheological evaluation indicated formulation followed Non-Newtonian system with shear thickening behavior. Particle size was found to be between 673.83 to 798.76 nm and poly-dispersity index was between 0.438 to 0.681. Microscopic analysis by Cryo-SEM analysis of the formulation showed stable homogeneous nature of formulation. Stability of the formulations was confirmed by freeze-thawing, dilution test and emulsion stability index. Acute oral toxicity study as per OECD guideline showed safety of the formulations. Most importantly, in vivo bioavailability study of ω-3 FA confirmed better bioavailability of the metabolites of ω-3 FA i.e. eicosapentaenoic and docosahexaenoic acids in formulation treated group as compared to flax oil and comparable bioavailability to that of fish oil.

In silico design of peptides with binding to the receptor binding domain (RBD) of the SARS-CoV-2 and their utility in bio-sensor development for SARS-CoV-2 detection.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people across the globe and created not only a health emergency but also a financial crisis. This virus attacks the angiotensin-converting enzyme 2 (ACE2) receptor situated on the surface of the host cell membrane. The spike protein of the virus binds to this receptor which is a critical step in infection. A molecule which can specifically stop this binding could be a potential therapeutic agent. In this study, we have tested 12 potential peptides which can bind to the receptor binding domain (RBD) of the spike protein of the virus and thus can potentially inhibit the binding of the latter on ACE2 receptors. These peptides are screened based on their binding with the RBD of the spike protein and aqueous stability, obtained using several atomistic molecular dynamic simulations. The potential of mean force calculation of peptides confirmed their binding to the RBD of the spike protein. Furthermore, two potential peptides were tested for use in a biosensing application for SARS-CoV-2 detection. Two types of biosensing platforms, a graphene sheet and a carbon nano tube (CNT) were tested. The peptides were modified in order to functionalize the graphene and CNT. Based on the interaction between the substrate, peptide and spike protein, the utility of the screened peptide for a given bio sensing platform is discussed and recommended.

Development and application of coarse-grained MARTINI model of skin lipid ceramide [AP].

Stratum corneum (SC), the outermost layer of the skin, contains large variety of lipids, endowing them with the amphiphilic properties, needed to fulfil their key role in skin's barrier function. The individual role of lipid types in the barrier function is difficult to understand due to the immense heterogeneity and complexity of the lipid's organization within the SC. The lipid organization is being explored using both computational (molecular dynamics simulations) and experimental (neutron diffraction) techniques. Even though atomistic simulations provide unprecedented atomic level details, the major limitation is time and length scale that can be achieved with decent computational facility. Alternatively, coarse-grain (CG) models are currently being used to capture physics at bigger time and length scale without losing essential underlined structural information. In this study, a CG model of α-hydroxy phytosphingosines (CER[AP]) is developed based on philosophy of MARTINI force field. At first, the model is validated with various atomistic simulations and available experimental data. Later on, the model's compatibility with other major skin lipids, cholesterol, and free fatty acid (palmitic acid) is checked by simulating a mixture of lipid multilayer in presence and absence of water. The developed model of CER[AP] is able to predict key structural properties within the acceptable error limits. The phenomena of ceramide conformation transformation, cholesterol flip-flop, and specificity of lipid arrangement within the multilayered systems is observed during the simulation. This signifies the importance of model in capturing higher order structural transformations.

Permeation of nanoparticles across the intestinal lipid membrane: dependence on shape and surface chemistry studied through molecular simulations.

Nanoparticles are being explored for topical and oral drug delivery applications as they can cross various biological barriers, for example, the intestinal epithelium. The ability of nanoparticles to cross barriers depends on their morphological and surface properties such as size, surface chemistry and shape, among others. The effect of nanoparticle size on their membrane permeability has been well studied both experimentally and theoretically. However, less attention has been given to understand the role of nanoparticle shape in their translocation across biological barrier membranes. Here, we report on the influence of the nanoparticle's shape, surface chemistry and concentration on their permeation across a human intestinal apical cell membrane model. A representative multicomponent lipid bilayer model of the human intestinal apical membrane was built. The free energy of permeation of nanoparticles across the model lipid bilayer was calculated using multiple umbrella sampling simulations. The interaction of these nanoparticles with the model lipid bilayer was captured using extensive microsecond unrestrained molecular dynamics simulations. We observed that: (a) irrespective of the surface chemistry, the efficacy of nanoparticle penetration across the lipid layer was in the order of rod > disc > sphere; (b) irrespective of the shape, apolar and nonpolar nanoparticles were found to locate in the interior of the lipid bilayer, whereas charged and polar nanoparticles were either adsorbed on the lipid headgroups or remained in the water layer; (c) apolar and nonpolar disc shaped nanoparticles had higher efficacy in permeation across the lipid bilayer as compared to disc and sphere shaped nanoparticles; and (d) at a higher concentration of nanoparticles, sphere and disc shaped nanoparticles exhibited more agglomeration as compared to rod shaped nanoparticles. Based on these outcomes, a few nanoparticles were designed which penetrated readily into the lipid layer and these nanoparticles were also able to co-deliver a therapeutic protein inside the lipid layer. The apical model lipid membrane and protocols used in this study can thus be utilized for the in silico design of nanoparticles for the oral delivery of therapeutics.

Molecular mechanism of the skin permeation enhancing effect of ethanol: a molecular dynamics study.

Ethanol is widely used in various pharmaceutical and cosmetic formulations in order to enhance skin penetration of active ingredients. While it is well known that ethanol partitions into the skin and enhances the permeation of both polar and nonpolar molecules, the exact mechanisms by which it enhances skin permeability are not fully understood. Several mechanisms have been proposed including lipid extraction from the stratum corneum (SC), fluidisation of SC lipid bilayer, alteration of SC protein conformation and enhancement of the drug solubility in the SC lipids. In this study, we performed molecular dynamics (MD) simulations of SC lipid bilayers comprised of an equimolar mixture of ceramides, cholesterol and free fatty acid in the presence of aqueous mixtures of ethanol. Various unrestrained MD simulations were performed in the presence of aqueous ethanol solution at molar ratios (x) ranging from x = 0 to x = 1. It was found that ethanol enhances bilayer permeability by dual actions (a) extraction of the skin lipids and (b) enhancing the mobility of lipid chains. Ethanol's permeation enhancing effect arises from its superior ability to form hydrogen bonds with headgroup atoms of skin lipids. Further, the free energy of extraction of ceramides (CER) and fatty acids (FFA) from the lipid bilayer was studied using umbrella sampling simulations. The free energy of extraction of CER was found to be much higher compared to FFA for all ethanol concentrations which shows that CER are difficult to extract as compared to FFA. Finally, the permeation of benzoic acid drug molecules through the skin lipid bilayer is shown in presence of ethanol molecules. It was found that ethanol selectively targets the FFA of the skin lipid bilayer and extracts it out of the lipid bilayer within few microseconds. Further, ethanol penetrates inside the lipid layer and creates the channels from which drug molecules can easily cross the lipid layer. Our observations (both in unrestrained and umbrella sampling simulations) are consistent with the experimental findings reported in the literature. The simulation methodology could be used for design and testing of permeation enhancers (acting on skin SC lipid lamella) for topical and transdermal drug delivery applications.

Structural and barrier properties of the skin ceramide lipid bilayer: a molecular dynamics simulation study.

Skin provides excellent protection against the harsh external environment and foreign substances. The lipid matrix of the stratum corneum, which contains various kinds of ceramides, plays a major role in the barrier function of the skin. Here we report a study of the effects of ceramide type on the structural and transport properties of ceramide bilayers using molecular dynamics (MD) simulations. Specifically, the effects of headgroup chemistry (number and positions of hydroxyl groups) and tail structure (unsaturation of the sphingoid moiety) on the structural and transport properties of various ceramide bilayers at 310 K were analyzed. Theoretical results for structural properties such as area per lipid, bilayer thickness, lateral arrangement, order parameter, and hydrogen bonding are reported here and compared with corresponding experimental data. Our study revealed that the presence of a double bond disrupts the bilayer packing, which leads to a low area compressibility modulus, a large area per lipid, and low bilayer thickness. Furthermore, the effect of structural changes on water permeation was studied using steered MD simulations. Water permeation was found to be influenced by headgroup polarity, chain packing, and the ability of the water to hydrogen bond with the ceramides. The molecular-level information obtained from the current study should aid the design of mixed bilayer systems with desired properties and provide the basis for the development of higher order coarse-grained models.