This manuscript reports a detailed study on the ability of poly(vinyl alcohol) to act as a biomimetic surrogate for antifreeze(glyco)proteins, with a focus on the specific property of ice-recrystallization inhibition (IRI). Despite over 40 years of study, the underlying mechanisms that govern the action of biological antifreezes are still poorly understood, which is in part due to their limited availability and challenging synthesis. Poly(vinyl alcohol) (PVA) has been shown to display remarkable ice recrystallization inhibition activity despite its major structural differences to native antifreeze proteins. Here, controlled radical polymerization is used to synthesize well-defined PVA, which has enabled us to obtain the first quantitative structure-activity relationships, to probe the role of molecular weight and comonomers on IRI activity. Crucially, it was found that IRI activity is "switched on" when the polymer chain length increases from 10 and 20 repeat units. Substitution of the polymer side chains with hydrophilic or hydrophobic units was found to diminish activity. Hydrophobic modifications to the backbone were slightly more tolerated than side chain modifications, which implies an unbroken sequence of hydroxyl units is necessary for activity. These results highlight that, although hydrophobic domains are key components of IRI activity, the random inclusion of addition hydrophobic units does not guarantee an increase in activity and that the actual polymer conformation is important.

Bradford Scholars -how to deposit your paper Overview Copyright check• Check if your publisher allows submission to a repository.• Use the Sherpa RoMEO database if you are not sure about your publisher's position or email openaccess@bradford.ac.uk.

The lipids of the topmost layer of the skin, the stratum corneum, represent the primary barrier to molecules penetrating the skin. One approach to overcoming this barrier for the purpose of delivery of active molecules into or via the skin is to employ chemical permeability enhancers, such as dimethylsulfoxide (DMSO). How these molecules exert their effect at the molecular level is not understood. We have investigated the interaction of DMSO with gel-phase bilayers of ceramide 2, the predominant lipid in the stratum corneum, by means of molecular dynamics simulations. The simulations satisfactorily reproduce the phase behavior and the known structural parameters of ceramide 2 bilayers in water. The effect of DMSO on the gel-phase bilayers was investigated at various concentrations over the range 0.0-0.6 mol fraction DMSO. The DMSO molecules accumulate in the headgroup region and weaken the lateral forces between the ceramides. At high concentrations of DMSO (> or =0.4 mol fraction), the ceramide bilayers undergo a phase transition from the gel phase to the liquid crystalline phase. The liquid-crystalline phase of ceramides is expected to be markedly more permeable to solutes than the gel phase. The results are consistent with the experimental evidence that high concentrations of DMSO fluidize the stratum corneum lipids and enhance permeability.

The interactions of silica surfaces with water and biomolecules are of considerable significance in bio- and nanotechnology and in geochemistry. An important goal in the fields of biomineralization and biomimetics is to fine-tune these interactions for the control, e.g., of assembly of materials at the nanoscale. Here we report molecular dynamics simulations of fully hydroxylated alpha-quartz (1010), (0001), and (0111) surfaces in explicit water. We also present free energy estimates of adsorbing water and analogues of amino acid side chains onto the quartz (1010) surface. We find that at least two layers of structured water form on the surface, which is driven by the formation of a strong hydrogen bond network at the interface. Interestingly, we find that the free energy change to move methane (analogue of the side chain of alanine) from bulk water to the (1010) interface is favorable. We ascribe this to the presence of microscopic voids on the surface, which can accommodate small hydrophobic moieties and shield them from the solvent. These observations draw some useful insights into the possible mechanisms by which biomolecules, in particular peptides and proteins, bind to quartz and other silica surfaces.

Understanding the mechanisms of biomineralization and the realization of biology-inspired inorganic materials formation largely depends on our ability to manipulate peptide/solid interfacial interactions. Material interfaces and biointerfaces are critical sites for bioinorganic synthesis, surface diffusion, and molecular recognition. Recently adapted biocombinatorial techniques permit the isolation of peptides recognizing inorganic solids that are used as molecular building blocks, for example, as synthesizers, linkers, and assemblers. Despite their ubiquitous utility in nanotechnology, biotechnology, and medicine, the fundamental mechanisms of molecular recognition of engineered peptides binding to inorganic surfaces remain largely unknown. To explore propensity rules connecting sequence, structure, and function that play key roles in peptide/solid interactions, we combine two different approaches: a statistical analysis that searches for highly enriched motifs among de novo designed peptides, and, atomistic simulations of three experimentally validated peptides. The two strong and one weak quartz-binding peptides were chosen for the simulations at the quartz (100) surface under aqueous conditions. Solution-based peptide structures were analyzed by circular dichroism measurements. Small and hydrophobic residues, such as Pro, play a key role at the interface by making close contact with the solid and hindering formation of intrapeptide hydrogen bonds. The high binding affinity of a peptide may be driven by a combination of favorable enthalpic and entropic effects, that is, a strong binder may possess a large number of possible binding configurations, many of which having relatively high binding energies. The results signify the role of the local molecular environment among the critical residues that participate in solid binding. The work herein describes molecular conformations inherent in material-specific peptides and provides fundamental insight into the atomistic understanding of peptide/solid interfaces.

No abstract

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.

An understanding of how molecules permeate the complex lipid matrix of the stratum corneum (SC) skin barrier is important for transdermal drug delivery, preventing the adsorption of toxic chemicals and tackling skin diseases. In this paper we present atomistic molecular dynamics simulations of skin-lipid bilayers composed of ceramides, cholesterol (CHOL) and free fatty acids at different lipid compositions and levels of hydration and investigate both perpendicular and lateral permeation pathways through the systems. We show that in fully hydrated bilayers the lipids are heterogeneously distributed, with CHOL-rich domains emerging spontaneously during the simulations. Potential of mean constraint force calculations reveal that the most favourable permeation pathway for water in the direction normal to the bilayer is through a CHOL-rich region, probably due to the disordering effect of CHOL on lipids in the gel-phase. In systems with a low water content (akin to real skin) we find that rather than forming continuous layers, water forms flattened ellipsoid-shaped pools between the lipid headgroups, which are separated by dry regions. This implies that there is no continuous aqueous lateral pathway in the SC and may help to explain why skin is such an effective barrier. We propose that the most probable permeation pathway for a small polar molecule consists of hopping from the headgroup region of one bilayer to the next via a dry region, followed by permeation along the bilayer normal through a CHOL-rich region to the centre of the bilayer where it can diffuse laterally in the lower-density lipidic environment before encountering another CHOL-rich region through which it can exit the bilayer.