Locked by Design: A Conformationally Constrained Transglutaminase Tag Enables Efficient Site‐Specific Conjugation

Based on the crystal structure of a natural protein substrate for microbial transglutaminase, an enzyme that catalyzes protein crosslinking, a recognition motif for site‐specific conjugation was rationally designed. Conformationally locked by an intramolecular disulfide bond, this structural mimic of a native conjugation site ensured efficient conjugation of a reporter cargo to the therapeutic monoclonal antibody cetuximab without erosion of its binding properties.     

Extending the hydrophobic cavity of β-cyclodextrin results in more negative heat capacity changes but reduced binding affinities

The formation of inclusion complexes of hydroxypropylated β-cyclodextrins (CDs) with three bile salts are investigated to shed light on the role played by the hydroxypropyl (HP) substituents. The HP-chains are situated at the rim of the CD and may thus extend the hydrophobic cavity of the CD. Calorimetric titrations in a broad temperature range and molecular dynamics simulations confirm previous speculations that the HP-chains cause an increase in dehydrated nonpolar surface area upon formation of the complexes. This additional burial of nonpolar surface area, 12–16 Å² per HP-chain according to the MD simulations, results in more negative values of ΔC _p °, which are in quantitative agreement with what is expected for hydrophobic dehydration. Although these observations support the picture of an extended hydrophobic cavity, HPβCD complexes were less stable than their unsubstituted counterparts. This indicates that increased hydrophobic contacts are not always accompanied by increased binding strength. The linear dependence of ΔC _p °, ΔH° and ΔS° on the number of HP-chains give rise to isoentropic and isoenthalpic temperatures at which ΔH° and ΔS° are independent of the number of HP-chains on the host CD (but depend on the type of bile salt). Interestingly, these convergence temperatures are close to what is observed for unfolding of proteins and may be a common feature of hydrophobic dehydration.     

Multifunctional Cationic PeptoStars as siRNA Carrier: Influence of Architecture and Histidine Modification on Knockdown Potential

RNA interference provides enormous potential for the treatment of several diseases, including cancer. Nevertheless, successful therapies based on siRNA require overcoming various challenges, such as poor pharmacokinetic characteristics of the small RNA molecule and inefficient cytosolic accumulation. In this respect, the development of functional siRNA carrier systems is a major task in biomedical research. To provide such a desired system, the synthesis of 3‐arm and 6‐arm PeptoStars is aimed for. The different branched polypept(o)idic architectures share a stealth‐like polysarcosine corona for efficient shielding and a multifunctional polylysine core, which can be independently varied in size and functionality for siRNA complexation‐, transport and intra cellular release. The special feature of star‐like polypept(o)ides is in their uniform small size (<20 nm) and a core–shell structure, which implies a high stability and stealth‐like properties and thus, they may combine long circulation times and a deep penetration of cancerous tissue. Initial toxicity and complement studies demonstrate well tolerated cationic PeptoStars with high complexation capability toward siRNA (N/P ratio up to 3:1), which can lead to potent RNAi for optimized systems. Here, the synthetic development of 3‐arm and 6‐arm polypept(o)idic star polymers, their modification with endosomolytic moieties, and first in vitro insights on RNA interference are reported on.     

The retro Grignard addition reaction revisited: the reversible addition of benzyl reagents to ketones

The Grignard addition reaction is known to be a reversible process with allylic reagents, but so far the reversibility has not been demonstrated with other alkylmagnesium halides. By using crossover experiments it has been established that the benzyl addition reaction is also a reversible transformation. The retro benzyl reaction was shown by the addition of benzylmagnesium chloride to di-tert-butyl ketone followed by exchange of both the benzyl and the ketone moiety with another substrate. Similar experiments were performed with phenylmagnesium bromide and tert-butylmagnesium chloride, but in these two cases the Grignard addition reaction did not show any sign of a reverse transformation.     

The Momentum Map Representation of Images

This paper discusses the mathematical framework for designing methods of Large Deformation Diffeomorphic Matching (LDM) for image registration in computational anatomy. After reviewing the geometrical framework of LDM image registration methods, we prove a theorem showing that these methods may be designed by using the actions of diffeomorphisms on the image data structure to define their associated momentum representations as (cotangent-lift) momentum maps. To illustrate its use, the momentum map theorem is shown to recover the known algorithms for matching landmarks, scalar images, and vector fields. After briefly discussing the use of this approach for diffusion tensor (DT) images, we explain how to use momentum maps in the design of registration algorithms for more general data structures. For example, we extend our methods to determine the corresponding momentum map for registration using semidirect product groups, for the purpose of matching images at two different length scales. Finally, we discuss the use of momentum maps in the design of image registration algorithms when the image data is defined on manifolds instead of vector spaces.     

Structure factor of ferrofluids with chain aggregates: Theory and computer simulations

In this paper we present theoretical and simulation results on the structure factor of mono- and bidisperse ferrofluids with chain aggregates, both with and without an applied external magnetic field. Chain distribution is obtained by the density functional theory (DFT). The radial distribution function (RDF) is calculated directly on the basis of the chain distribution and Fourier transformed to calculate the structure factor. An extensive comparison of the theoretical predictions to the results of the molecular dynamics computer simulations is provided. The proposed combined approach allows to elucidate the connection between experimentally observed small angle neutron scattering (SANS) images and the ferrofluid microstructure.