Electron affinity | EPFL Graph Search

The electron affinity (Eea) of an atom or molecule is defined as the amount of energy released when an electron attaches to a neutral atom or molecule in the gaseous state to form an anion. ::X(g) + e− → X−(g) + energy This differs by sign from the energy change of electron capture ionization. The electron affinity is positive when energy is released on electron capture. In solid state physics, the electron affinity for a surface is defined somewhat differently (see below). Measurement and use of electron affinity This property is used to measure atoms and molecules in the gaseous state only, since in a solid or liquid state their energy levels would be changed by contact with other atoms or molecules. A list of the electron affinities was used by Robert S. Mulliken to develop an electronegativity scale for atoms, equal to the average of the electrons affinity and ionization potential. Other theoretical concepts that use electron affinity inc

New methods for developing (bi)cyclic peptides by phage display

Camille Villequey

Cyclic peptide ligands are a promising molecular format for the development of therapeutics. They combine some of the advantages of large protein therapeutics (high affinity and specificity) and of small molecule drugs (accessibility to chemical synthesis and low immunogenicity). With phage display, large combinatorial libraries of more than one billion mono- and polycyclic peptides can be developed and screened against virtually any target. During phage affinity selections, the physical link between phenotype (encoded peptide) and genotype (phage DNA) allows the identification of enriched peptide binders by sequencing of the phage vector DNA. Based on these concepts, our laboratory has established a robust chemistry in which phage displayed peptides containing two or three cysteines are cyclized or bi-cyclized with thiol-reactive linkers. This procedure has been generally applied for the isolation of potent and selective (bi)cyclic peptide ligands with therapeutic potential. The isolation of binders with optimal properties is highly dependent on the possibility to generate (bi)cyclic peptide libraries with high structural diversity and on the ability to thoroughly decode the phage selection output. In my PhD work, I developed new methods to generate large and structurally diverse libraries and to decode more efficiently phage selected peptides. In my first project, I explore the cyclization of peptides with two chemical bridges as a method to provide rapid access to phage-encoded libraries with high scaffold diversity. To this end, a range of twelve structurally diverse chemicals were tested for thiol-reactivity and phage compatibility. Subsequently, peptide libraries of the format XCXnCXnCX (X = random amino acid, C = cysteine, n = 3 or 4) were cyclized with six of these chemical linkers and panned against the protease plasma kallikrein. The selection yielded inhibitors with remarkable affinity (sub-nM KI), target selectivity (>1000-fold) and proteolytic stability (t1/2 in plasma > 3 days) despite a relatively small molecular mass (~ 1200 Da). In the second project, I developed phage-encoded libraries of small cyclic peptides in order to identify ligands that have the potential to be orally absorbed. A major challenge for the generation of such library is the usually low diversity of compounds due to the limited number of amino acids. In this work, we addressed this limitation by taking advantage of a recently discovered peptide cyclization reaction in which the thiol of a cysteine is ligated with the N-terminal amino group using a chemical reagent. We applied this strategies to two phage-encoded peptide libraries of four and five amino acids (XXXC and XXXXC) that were cyclized with eight chemical linkers yielding a collection of more than 1.3 million compounds. Panning the libraries against the two disease targets plasma kallikrein and coagulation factor XIa yielded ligands with single-digit micromolar affinity. In a third project, I developed a strategy to bypass the bacterial infection step in phage display. Bacterial infection is usually crucial for the propagation and identification of enriched clones by DNA sequencing. However, mutations or chemical modifications of the phage coat proteins, sometimes lead to decreased infection rates and therefore compromise the entire procedure. Consequently, there is an interest for developing methods in which this step could be completely omitted.

EPFL2017

Reinforcing hydrogels with in situ formed amorphous CaCO3

Esther Amstad, Huachuan Du, Matteo Hirsch, Michael David Kessler, Tianyu Yuan, Ran Zhao

Hydrogels are often employed for tissue engineering and moistening applications. However, they are rarely used for load-bearing purposes because of their limited stiffness and the stiffness-toughness compromise inherent to them. By contrast, nature uses hydrogel-based materials as scaffolds for load-bearing and protecting materials by mineralizing them. Inspired by nature, the stiffness or toughness of synthetic hydrogels has been increased by forming minerals, such as CaCO3, within them. However, the degree of hydrogel reinforcement achieved with CaCO3 remains limited. To address this limitation, we form CaCO3 biominerals in situ within a model hydrogel, poly(acrylamide) (PAM), and systematically investigate the influence of the size, structure, and morphology of the reinforcing CaCO3 on the mechanical properties of the resulting hydrogels. We demonstrate that especially the structure of CaCO3 and its affinity to the hydrogel matrix strongly influence the mechanical properties of mineralized hydrogels. For example, while the fracture energy of PAM hydrogels is increased 3-fold if reinforced with individual micro-sized CaCO3 crystals, it increases by a factor of 13 if reinforced with a percolating amorphous calcium carbonate (ACC) nano-structure that forms in the presence of a sufficient quantity of Mg2+. If PAM is further functionalized with acrylic acid (AA) that possesses a high affinity towards ACC, the stiffness of the hydrogel increases by a factor 50. These fundamental insights on the structure-mechanical property relationship of hydrogels that have been functionalized with in situ formed minerals has the potential to enable tuning the mechanical properties of mineralized hydrogels over a much wider range than what is currently possible.

ROYAL SOC CHEMISTRY2022

New methods for developing (bi)cyclic peptides by phage display

Camille Villequey

EPFL2017