How Ethanolic Disinfectants Disintegrate Coronavirus Model Membranes: A Dissipative Particle Dynamics Simulation Study.

We have developed dissipative particle dynamics models for pure dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylcholine (DOPC), and dimyristoylphosphatidylcholine (DMPC) as well as their binary and ternary mixed membranes, as coronavirus model membranes. The stabilities of pure and mixed membranes, surrounded by aqueous solutions containing up to 70 mol % ethanol (alcoholic disinfectants), have been investigated at room temperature. We found that aqueous solutions containing 5-10 mol % ethanol already have a significant weakening effect on the pure and mixed membranes. The magnitude of the effect depends on the membrane composition and the ethanol concentration. Ethanol permeabilizes the membrane, causing its lateral swelling and thickness shrinking and reducing the orientational order of the hydrocarbon tail of the bilayer. The free energy barrier for the permeation of ethanol in the bilayers is considerably reduced by the ethanol uptake. The rupture-critical ethanol concentrations causing the membrane failure are 20.7, 27.5, and 31.7 mol % in the aqueous phase surrounding pure DMPC, DOPC, and DPPC membranes, respectively. Characterizing the failure of lipid membranes by a machine-learning neural network framework, we found that all mixed binary and/or ternary membranes disrupt when immersed in an aqueous solution containing a rupture-critical ethanol concentration, ranging from 20.7 to 31.7 mol %, depending on the composition of the membrane; the DPPC-rich membranes are more intact, while the DMPC-rich membranes are least intact. Due to the tight packing of long, saturated hydrocarbon tails in DPPC, increasing the DPPC content of the mixed membrane increases its stability against the disinfectant. At high DPPC concentrations, where the DOPC and DMPC molecules are confined between the DPPC lipids, the ordered hydrocarbon tails of DPPC also induce order in the DOPC and DMPC molecules and, hence, stabilize the membrane more. Our simulations on pure and mixed membranes of a diversity of compositions reveal that a maximum ethanol concentration of 32 mol % (55 wt %) in the alcohol-based disinfectants is enough to disintegrate any membrane composed of these three lipids.

The role of the envelope protein in the stability of a coronavirus model membrane against an ethanolic disinfectant.

Ethanol is highly effective against various enveloped viruses and can disable the virus by disintegrating the protective envelope surrounding it. The interactions between the coronavirus envelope (E) protein and its membrane environment play key roles in the stability and function of the viral envelope. By using molecular dynamics simulation, we explore the underlying mechanism of ethanol-induced disruption of a model coronavirus membrane and, in detail, interactions of the E-protein and lipids. We model the membrane bilayer as N-palmitoyl-sphingomyelin and 1-palmitoyl-2-oleoylphosphatidylcholine lipids and the coronavirus E-protein. The study reveals that ethanol causes an increase in the lateral area of the bilayer along with thinning of the bilayer membrane and orientational disordering of lipid tails. Ethanol resides at the head-tail region of the membrane and enhances bilayer permeability. We found an envelope-protein-mediated increase in the ordering of lipid tails. Our simulations also provide important insights into the orientation of the envelope protein in a model membrane environment. At ∼25 mol. % of ethanol in the surrounding ethanol-water phase, we observe disintegration of the lipid bilayer and dislocation of the E-protein from the membrane environment.

How Alcoholic Disinfectants Affect Coronavirus Model Membranes: Membrane Fluidity, Permeability, and Disintegration.

Atomistic molecular dynamics simulations have been carried out with a view to investigating the stability of the SARS-CoV-2 exterior membrane with respect to two common disinfectants, namely, aqueous solutions of ethanol and n-propanol. We used dipalmitoylphosphatidylcholine (DPPC) as a model membrane material and did simulations on both gel and liquid crystalline phases of membrane surrounded by aqueous solutions of varying alcohol concentrations (up to 17.5 mol %). While a moderate effect of alcohol on the gel phase of membrane is observed, its liquid crystalline phase is shown to be influenced dramatically by either alcohol. Our results show that aqueous solutions of only 5 and 10 mol % alcohol already have significant weakening effects on the membrane. The effects of n-propanol are always stronger than those of ethanol. The membrane changes its structure, when exposed to disinfectant solutions; uptake of alcohol causes it to swell laterally but to shrink vertically. At the same time, the orientational order of lipid tails decreases significantly. Metadynamics and grand-canonical ensemble simulations were done to calculate the free-energy profiles for permeation of alcohol and alcohol/water solubility in the DPPC. We found that the free-energy barrier to permeation of the DPPC liquid crystalline phase by all permeants is significantly lowered by alcohol uptake. At a disinfectant concentration of 10 mol %, it becomes insignificant enough to allow almost free passage of the disinfectant to the inside of the virus to cause damage there. It should be noted that the disinfectant also causes the barrier for water permeation to drop. Furthermore, the shrinking of the membrane thickness shortens the gap needed to be crossed by penetrants from outside the virus into its core. The lateral swelling also increases the average distance between head groups, which is a secondary barrier to membrane penetration, and hence further increases the penetration by disinfectants. At alcohol concentrations in the disinfectant solution above 15 mol %, we reliably observe disintegration of the DPPC membrane in its liquid crystalline phase.

Exploring the binding sites and binding mechanism for hydrotrope encapsulated griseofulvin drug on γ-tubulin protein.

The protein γ-tubulin plays an important role in centrosomal clustering and this makes it an attractive therapeutic target for treating cancers. Griseofulvin, an antifungal drug, has recently been used to inhibit proliferation of various types of cancer cells. It can also affect the microtubule dynamics by targeting the γ-tubulin protein. So far, the binding pockets of γ-tubulin protein are not properly identified and the exact mechanism by which the drug binds to it is an area of intense speculation and research. The aim of the present study is to investigate the binding mechanism and binding affinity of griseofulvin on γ-tubulin protein using classical molecular dynamics simulations. Since the drug griseofulvin is sparingly soluble in water, here we also present a promising approach for formulating and achieving delivery of hydrophobic griseofulvin drug via hydrotrope sodium cumene sulfonate (SCS) cluster. We observe that the binding pockets of γ-tubulin protein are mainly formed by the H8, H9 helices and S7, S8, S14 strands and the hydrophobic interactions between the drug and γ-tubulin protein drive the binding process. The release of the drug griseofulvin from the SCS cluster is confirmed by the coordination number analysis. We also find hydrotrope-induced alteration of the binding sites of γ-tubulin protein and the weakening of the drug-protein interactions.

Hydrotropic Solubilization of Sparingly Soluble Riboflavin Drug Molecule in Aqueous Nicotinamide Solution.

We study the effect of hydrotrope nicotinamide on the solubilization of sparingly soluble riboflavin drug molecule. Nicotinamide molecules self-associate through stacking of their pyridine rings, and they also form complexes with riboflavin molecules. Water molecules only prefer to stay at the periphery of the riboflavin molecules, and they are replaced by the hydrotrope molecules with increasing concentration of the solution. The analyses of orientation distributions and distance measurements reveal that the riboflavin and nicotinamide molecules form 1:2 sandwich complexes. It is demonstrated that the self-aggregation of nicotinamide and the complexation between riboflavin and nicotinamide does not have much influence on the number of water-water average hydrogen bonds but they influence the riboflavin-water, nicotinamide-water, riboflavin-riboflavin, riboflavin-nicotinamide, and nicotinamide-nicotinamide hydrogen bonds. Favorable van der Waals interaction energy between riboflavin and nicotinamide plays an important role in the 1:1 or 1:2 complex formation between drug and hydrotrope molecules. The electrostatic energy component of drug and hydrotrope interaction also contributes to the solubilization process. The negative Flory-Huggins interaction parameter value suggests the favorable interactions between the hydrotrope and drug molecules.

Hydrotropic Action of Cationic Hydrotrope p-Toluidinium Chloride on the Solubility of Sparingly Soluble Gliclazide Drug Molecule: A Computational Study.

We perform classical molecular dynamics simulations of sparingly soluble drug gliclazide (GLC) and hydrotrope p-toluidinium chloride (PTOL) in water with a regime of PTOL concentrations. Our results demonstrate that PTOL starts to self-aggregate above its minimum hydrotrope concentration (MHC). Further, these PTOL aggregates create a mixed micellar-like framework in which the hydrophobic small tail part of most of the PTOL molecules direct toward the inside, whereas in order to make favorable contact with water molecules its hydrophilic ammonium group points outward. But, in order to make hydrogen bonds with GLC molecules, the polar groups of a few of the hydrotropes direct inward also. This provides an environment for the incorporation of the drug molecules into the mixed environment (hydrophobic as well as hydrophilic core) of PTOL clusters. The average number of hydrogen bond calculations indicates that PTOL aggregate does not have much effect on the average number of water-PTOL hydrogen bonds, but it has an influence on the average number of water-GLC, GLC-GLC, and GLC-PTOL hydrogen bonds. Both electrostatic and van der Waals energy components of drug and hydrotrope interactions play vital roles in the solubilization process. Furthermore, the estimation of Flory-Huggins interaction parameters also suggests favorable interactions between hydrotrope PTOL and GLC drug molecules.

Computer Simulation Studies of the Mechanism of Hydrotrope-Assisted Solubilization of a Sparingly Soluble Drug Molecule.

The effect of hydrotrope sodium cumene sulfonate (SCS) on the solubility of a sparingly water-soluble drug, griseofulvin, is studied by employing classical molecular dynamics simulation technique. We mainly focus on the underlying mechanism by which SCS enhances the solubility of a sparingly soluble or insoluble solute in water. The main observations are the following: (a) The self-aggregation of SCS molecules (through its hydrophobic tail) above the minimum hydrotrope concentration (MHC) causes the formation of micellar-like frameworks. Interestingly, though the drug griseofulvin possesses both polar and nonpolar groups, it prefers to get encapsulated inside the hydrophobic core of SCS aggregates. The decomposition of total SCS-drug interaction energy into van der Waals and electrostatic components suggests that the former plays a major role in this interaction. (b) The calculated Flory-Huggins interaction parameter values give a strong indication of the mixing ability of hydrotrope SCS and griseofulvin drug molecules. (c) As expected, we do not observe any strong effect of SCS aggregates on SCS-water and water-water average hydrogen-bond number, but it affects water-drug griseofulvin average hydrogen-bond number. With the help of these observations we try to elucidate the hydrotropic action of hydrotrope SCS on the solubility of drug griseofulvin.

Mechanism of Hydrotropic Action of Hydrotrope Sodium Cumene Sulfonate on the Solubility of Di-t-Butyl-Methane: A Molecular Dynamics Simulation Study.

Hydrotropes are special class of amphiphilic molecules that have an ability to solubilize the insoluble or sparingly soluble molecules in water. To find out the mechanism of hydrotropic action of hydrotropes on hydrophobic molecules, we have carried out classical molecular dynamics simulation of hydrophobic solute di-t-butyl-methane (DTBM) and hydrotrope sodium cumene sulfonate (SCS) in water with a regime of SCS concentrations. Our study demonstrates that, above the minimum hydrotrope concentration (MHC), the self-aggregation of SCS starts, and it creates a micellar-like environment in which the hydrophobic tail part of SCS points inward while its hydrophilic sulfonate group points outward to make favorable contact with water molecules. The formation of the hydrophobic core of SCS cluster creates a hydrophobic environment where the hydrophobic DTBM molecules are encapsulated. Interestingly, the determination of average water-SCS hydrogen bonds further suggests that the aggregate formation of SCS molecules has a negligible influence on it. Moreover, the calculations of Flory-Huggins interaction parameters also reveal favorable interactions between hydrotrope SCS and solute DTBM molecules. The implications of these findings on the mechanism of hydrotrope assisted enhanced solubility of hydrophobic molecules are discussed.

Exploring molecular insights into aggregation of hydrotrope sodium cumene sulfonate in aqueous solution: a molecular dynamics simulation study.

Hydrotropes are an important class of molecules that enhance the solubility of an otherwise insoluble or sparingly soluble solute in water. Besides this, hydrotropes are also known to self-assemble in aqueous solution and form aggregates. It is the hydrotrope aggregate that helps in solubilizing a solute molecule in water. In view of this, we try to understand the underlying mechanism of self-aggregation of hydrotrope sodium cumene sulfonate (SCS) in water. We have carried out classical molecular dynamics simulations of aqueous SCS solutions with a regime of concentrations. Moreover, to examine the effect of temperature change on SCS aggregation, if any, we consider four different temperatures ranging from 298 to 358 K. From the estimation of densities of different solutions we calculate apparent and partial molal volumes of the hydrotrope. The changes in these quantities increase sharply at a characteristic minimum hydrotrope concentration. The determination of molal expansibility at infinite dilution for different temperatures indicates the water structure breaking by SCS molecules, which is further confirmed by the calculations of water-water pair correlation functions. In comparison with typical surfactants in micelles, a slightly lower value of volumetric change upon aggregation per carbon atom suggests the formation of a more closely packed structure of hydrotrope aggregates. A close examination of different structural properties of hydrotrope solutions reveals that the hydrophobic interactions through their hydrophobic tails significantly contribute in hydrotrope aggregation,and the dehydration of hydrophobic tail at elevated temperatures is also visible. Remarkably, the aggregates have little or no impact on the average number of water-SCS hydrogen bonds.