Jamshed Anwar

Structure of ice crystallized from supercooled water

The freezing of water to ice is fundamentally important to fields as diverse as cloud formation to cryopreservation. At ambient conditions, ice is considered to exist in two crystalline forms: stable hexagonal ice and metastable cubic ice. Using X-ray diffraction data and Monte Carlo simulations, we show that ice that crystallizes homogeneously from supercooled water is neither of these phases. The resulting ice is disordered in one dimension and therefore possesses neither cubic nor hexagonal symmetry and is instead composed of randomly stacked layers of cubic and hexagonal sequences. We refer to this ice as stacking-disordered ice I. Stacking disorder and stacking faults have been reported earlier for metastable ice I, but only for ice crystallizing in mesopores and in samples recrystallized from high-pressure ice phases rather than in water droplets. Review of the literature reveals that almost all ice that has been identified as cubic ice in previous diffraction studies and generated in a variety of ways was most likely stacking-disordered ice I with varying degrees of stacking disorder. These findings highlight the need to reevaluate the physical and thermodynamic properties of this metastable ice as a function of the nature and extent of stacking disorder using well-characterized samples.

Defect-mediated trafficking across cell membranes:insights from in silico modeling

Institute of Macromolecular Compounds, Russian Academy of Sciences, Bolshoi Prospect 31, V.O., St. Petersburg, 199004 Russia, Computational Laboratory, Institute of Pharmaceutical Innovation, University of Bradford, Bradford, West Yorkshire BD7 1DP, U.K., Department of Physics, Tampere University of Technology, P.O. Box 692, FI-33101 Tampere, Finland, Aalto University, School of Science and Technology, Finland, and MEMPHYSsCenter for Biomembrane Physics, University of Southern Denmark, Odense, Denmark

The Human Skin Barrier Is Organized as Stacked Bilayers of Fully Extended Ceramides with Cholesterol Molecules Associated with the Ceramide Sphingoid Moiety

The skin barrier is fundamental to terrestrial life and its evolution; it upholds homeostasis and protects against the environment. Skin barrier capacity is controlled by lipids that fill the extracellular space of the skins surface layer--the stratum corneum. Here we report on the determination of the molecular organization of the skins lipid matrix in situ, in its near-native state, using a methodological approach combining very high magnification cryo-electron microscopy (EM) of vitreous skin section defocus series, molecular modeling, and EM simulation. The lipids are organized in an arrangement not previously described in a biological system-stacked bilayers of fully extended ceramides (CERs) with cholesterol molecules associated with the CER sphingoid moiety. This arrangement rationalizes the skins low permeability toward water and toward hydrophilic and lipophilic substances, as well as the skin barriers robustness toward hydration and dehydration, environmental temperature and pressure changes, stretching, compression, bending, and shearing.

Crystallization of polymorphs: the effect of solvent

The effect of solvent in crystallization of polymorphs has been studied using the drug sulphathiazole as a model compound. The solubilities of the four polymorphic forms of sulphathiazole were determined as a function of temperature in various solvents. Within the temperature ranges studied, the rank order of solubility of the polymorphs was the same in all solvent systems. On the basis of this knowledge of the temperature dependence of the solubilities, recrystallization experiments, in which the supersaturation was systematically varied, were carried out in an endeavour to isolate each of the polymorphic forms from each solvent system. These recrystallization experiments reveal that not all of the know polymorphic forms can be crystallized from any given solvent by varying the supersaturation. Indeed some solvents selectively favour the crystallization of a particular form of forms. The authors conclude that thermodynamic effects are not responsible for the selective behaviour of a solvent. A kinetic mechanism is proposed. It is considered that the solvent acts by selective adsorption to certain faces of some of the polymorphs, and thereby either inhibits their nucleation or retards their growth to the advantage of others.

Calculation of the melting point of NaCl by molecular simulation

We report a numerical calculation of the melting point of NaCl. The solid–liquid transition was located by determining the point where the chemical potentials of the solid and liquid phases intersect. To compute these chemical potentials, we made use of free energy calculations. For the solid phase the free energy was determined by thermodynamic integration from the Einstein crystal. For the liquid phase two distinct approaches were employed: one based on particle insertion and growth using the Kirkwood coupling parameter, and the other involving thermodynamic integration of the NaCl liquid to a Lennard-Jones fluid. The latter approach was found to be significantly more accurate. The coexistence point at 1074 K was characterized by a pressure of –30±40 MPa and a chemical potential of –97.9±0.2kβT. This result is remarkably good as the error bounds on the pressure enclose the expected coexistence pressure of about 0.1 MPa (ambient). Using the Clausius–Clapyron relation, we estimate that dP/dT ≈3 MPa/K. This yields a melting point of 1064±14 K at ambient pressure, which encompasses the quoted range for the experimental melting point (1072.45–1074.4 K). The good agreement with the experimental melting-point data provides additional evidence that the Tosi–Fumi model for NaCl is quite accurate. Our study illustrates that the melting point of an ionic system can be calculated accurately by employing a judicious combination of free energy techniques. The techniques used in this work can be directly extended to more complex, charged systems.

Breaching the skin barrier — Insights from molecular simulation of model membranes

Breaching the skins barrier function by design is an important strategy for delivering drugs and vaccines to the body. However, while there are many proposed approaches for reversibly breaching the skin barrier, our understanding of the molecular processes involved is still rudimentary. Molecular simulation offers an unprecedented molecular-level resolution with an ability to reproduce molecular and bulk level properties. We review the basis of the molecular simulation methodology and give applications of relevance to the skin lipid barrier, focusing on permeation of molecules and chemical approaches for breaching the lipid barrier by design. The bulk kinetic model based on Ficks Law describing absorption of a drug through skin has been reconciled with statistical mechanical quantities such as the local excess chemical potential and local diffusion coefficient within the membrane structure. Applications of molecular simulation reviewed include investigations of the structure and dynamics of simple models of skin lipids, calculation of the permeability of molecules in simple model membranes, and mechanisms of action of the penetration enhancers, DMSO, ethanol and oleic acid. The studies reviewed illustrate the power and potential of molecular simulation to yield important physical insights, inform and rationalize experimental studies, and to predict structural changes, and kinetic and thermodynamic quantities.

Mode of action and design rules for additives that modulate crystal nucleation.

Molecular dynamics simulations reveal that the key factors that determine the ability of an additive to modulate crystal nucleation are the strength of its interaction with the solute, its disruptive ability (which may be based on steric, entropic, or energetic effects), and interfacial properties, along with its ability to serve as a template for nucleation (see snapshot of an emerging nucleus with a single-particle additive: black spheres).

Nanofiber-Based Delivery of Therapeutic Peptides to the Brain

The delivery of therapeutic peptides and proteins to the central nervous system is the biggest challenge when developing effective neuropharmaceuticals. The central issue is that the blood-brain barrier is impermeable to most molecules. Here we demonstrate the concept of employing an amphiphilic derivative of a peptide to deliver the peptide into the brain. The key to success is that the amphiphilic peptide should by design self-assemble into nanofibers wherein the active peptide epitope is tightly wrapped around the nanofiber core. The nanofiber form appears to protect the amphiphilic peptide from degradation while in the plasma, and the amphiphilic nature of the peptide promotes its transport across the blood-brain barrier. Therapeutic brain levels of the amphiphilic peptide are achieved with this strategy, compared with the absence of detectable peptide in the brain and the consequent lack of a therapeutic response when the underivatized peptide is administered.

Molecular dynamics simulation of a polysorbate 80 micelle in water

The structure and dynamics of a single molecule of the nonionic surfactant polysorbate 80 (POE (20) sorbitan monooleate; Tween 80®) as well as a micelle comprising sixty molecules of polysorbate 80 in water have been investigated by molecular dynamics simulation. In its free state in water the polysorbate 80 molecule samples almost its entire conformational space. The micelle structure is compact and exhibits a prolate ellipsoid shape, with the surface being dominated by the polar terminal groups of the POE chains. The radius of gyration of the micelle was 26.2 A. The physical radius, determined from both the radius of gyration and atomic density, was about 35 A. The estimated diffusion constants for the free molecule (1.8 × 10−6 cm2s−1) and the micelle (1.8 × 10−7 cm2s−1) were found to be remarkably close to the respective experimental values. The lateral diffusion of the molecules on the micelle surface was estimated to be 1.7 × 10−7 cm2s−1, which confirms the highly dynamic nature of the micelle structure.

Simulations of Skin Barrier Function: Free Energies of Hydrophobic and Hydrophilic Transmembrane Pores in Ceramide Bilayers

Transmembrane pore formation is central to many biological processes such as ion transport, cell fusion, and viral infection. Furthermore, pore formation in the ceramide bilayers of the stratum corneum may be an important mechanism by which penetration enhancers such as dimethylsulfoxide (DMSO) weaken the barrier function of the skin. We have used the potential of mean constraint force (PMCF) method to calculate the free energy of pore formation in ceramide bilayers in both the innate gel phase and in the DMSO-induced fluidized state. Our simulations show that the fluid phase bilayers form archetypal water-filled hydrophilic pores similar to those observed in phospholipid bilayers. In contrast, the rigid gel-phase bilayers develop hydrophobic pores. At the relatively small pore diameters studied here, the hydrophobic pores are empty rather than filled with bulk water, suggesting that they do not compromise the barrier function of ceramide membranes. A phenomenological analysis suggests that these vapor pores are stable, below a critical radius, because the penalty of creating water-vapor and tail-vapor interfaces is lower than that of directly exposing the strongly hydrophobic tails to water. The PMCF free energy profile of the vapor pore supports this analysis. The simulations indicate that high DMSO concentrations drastically impair the barrier function of the skin by strongly reducing the free energy required for pore opening.