Cu2+-induced self-assembly and amyloid formation of a cyclic d,l-α-peptide: Structure and function

In a wide spectrum of neurodegenerative diseases, self-assembly of pathogenic proteins to cytotoxic intermediates is accelerated by the presence of metal ions such as Cu2+. Only low concentrations of these early transient oligomeric intermediates are present in a mixture of species during fibril formation, and hence information on the extent of structuring of these oligomers is still largely unknown. Here, we investigate dimers as the first intermediates in the Cu2+-driven aggregation of a cyclic D,L-alpha-peptide architecture. The unique structural and functional properties of this model system recapitulate the self-assembling properties of amyloidogenic proteins including beta-sheet conformation and cross-interaction with pathogenic amyloids. We show that a histidine-rich cyclic D,L-alpha-octapeptide binds Cu2+ with high affinity and selectivity to generate amyloid-like cross-beta-sheet structures. By taking advantage of backbone amide methylation to arrest the self-assembly at the dimeric stage, we obtain structural information and characterize the degree of local order for the dimer. We found that, while catalytic amounts of Cu2+ promote aggregation of the peptide to fibrillar structures, higher concentrations dose-dependently reduce fibrillization and lead to formation of spherical particles, showing self-assembly to different polymorphs. For the initial self-assembly step to the dimers, we found that Cu2+ is coordinated on average by two histidines, similar to self-assembled peptides, indicating that a similar binding interface is perpetuated during Cu2+-driven oligomerization. The dimer itself is found in heterogeneous conformations that undergo dynamic exchange, leading to the formation of different polymorphs at the initial stage of the aggregation process

Thermodynamic study of interactions between ZnO and ZnO binding peptides using isothermal titration calorimetry

Whilst material specific peptide binding sequences have been identified using a combination of combinato-rial methods and computational modelling tools, a deep molecular level understanding of the fundamental principles through which these interactions occur and in some instances modify the morphology of inorganic materials is far from being fully realized. Understanding the thermodynamic changes that occur during peptide-inorganic interactions and correlating these to structural modifications of the inorganic materials could be the key to achieving and mastering con-trol over material formation processes. This study is a detailed investigation applying isothermal titration calorimetry (ITC) to directly probe thermodynamic changes that occur during interaction of ZnO binding peptides (ZnO-BPs) and ZnO. The ZnO-BPs used are reported sequences G-12 (GLHVMHKVAPPR), GT-16 (GLHVMHKVAPPR-GGGC) and alanine mutants of G-12 (G-12A6, G-12A11 and G-12A12) whose interaction with ZnO during solution synthesis studies have been extensively investigated. The interactions of the ZnO-BPs with ZnO yielded biphasic isotherms comprising both an endo-thermic and an exothermic event. Qualitative differences were observed in the isothermal profiles of the different pep-tides and ZnO particles studied. Measured ΔG values were between -6 and -8.5 kcal/mol and high adsorption affinity val-ues indicated the occurrence of favourable ZnO-BP-ZnO interactions. ITC has great potential in its use to understand peptide-inorganic interactions and with continued development, the knowledge gained may be instrumental for simplifi-cation of selection processes of organic molecules for the advancement of material synthesis and design

Entropy of Molecular Binding at Solvated Mineral Surfaces

We present thermodynamic integration simulations for the binding of mannose and methanoic acid onto the {10.4} calcite surface producing free energy of binding values of −2.89 and −1.64 kJ mol–1, respectively. We extract the entropy of binding from vacuum-based simulations and use these values to determine the entropy of binding for surface water molecules which is ∼6 J mol–1 K–1

Spinning-frequency-dependent narrowband RF-driven dipolar recoupling

Dipolar recoupling techniques of homonuclear spin pairs are commonly used for distance or orientation measurements in solids. Accurate measurements are interfered with by broadening mechanisms. In this publication narrowband RF-driven dipolar recoupling magnetization exchange experiments are performed as a function of the spinning frequency to reduce the effect of zero-quantum T2 relaxation. To enhance the exchange of magnetization between the coupled spins, a fixed number of rotor-synchronous π-pulses are applied at spinning frequencies approaching the rotational resonance (R2) conditions. The analysis of the powder averaged dipolar decay curves of the spin magnetizations as a function of the spinning frequency provides a quantitative measure of the dipolar coupling. An effective Hamiltonian for this experiment is derived, taking into account all chemical shift parameters of the spins. The length of the nbRFDR mixing time and the number of rotor cycles per π-pulse are optimized by numerical simulations for sensitive probing of the dipolar coupling strength. The zero-quantum T2 relaxation time can easily be taken into account in the data analysis, because the overall exchange time is almost constant in these experiments. Spinning-frequency-depen-dent nbRFDR experiments near the m = 1 and m = 2 R2 condition are shown for doubly 13C-labeled hydroxybutyric acid

Folding of the C-terminal bacterial binding domain in statherin upon adsorption onto hydroxyapatite crystals

Statherin is an enamel pellicle protein that inhibits hydroxyapatite (HAP) nucleation and growth, lubricates the enamel surface, and is recognized by oral bacteria in periodontal diseases. We report here from solid-state NMR measurements that the protein's C-terminal region folds into an α-helix upon adsorption to HAP crystals. This region contains the binding sites for bacterial fimbriae that mediate bacterial cell adhesion to the surface of the tooth. The helical segment is shown through long-range distance measurements to fold back onto the intermediate region (residues Y16–P28) defining the global fold of the protein. Statherin, previously shown to be unstructured in solution, undergoes conformation selection on its substrate mineral surface. This surface-induced folding of statherin can be related to its functionality in inhibiting HAP crystal growth and can explain how oral pathogens selectively recognize HAP-bound statherin

Pushing the limit of layered transition metal oxide cathodes for high-energy density rechargeable Li ion batteries131

Development of advanced high energy density lithium ion batteries is important for promoting electromobility. Making electric vehicles attractive and competitive compared to conventional automobiles depends on the availability of reliable, safe, high power, and highly energetic batteries whose components are abundant and cost effective. Nickel rich Li[NixCoyMn1−x−y]O2 layered cathode materials (x > 0.5) are of interest because they can provide very high specific capacity without pushing charging potentials to levels that oxidize the electrolyte solutions. However, these cathode materials suffer from stability problems. We discovered that doping these materials with tungsten (1 mol%) remarkably increases their stability due to a partial layered to cubic (rock salt) phase transition. We demonstrate herein highly stable Li ion battery prototypes consisting of tungsten-stabilized Ni rich cathode materials (x > 0.9) with specific capacities >220 mA h g-1. This development can increase the energy density of Li ion batteries more than 30% above the state of the art without compromising durability