What prompted you to investigate this topic/problem? Protein aggregation and amyloid formation have become an important research area, as conformational change of proteins is at the root of many diseases (Alzheimer's &P arkinson's disease, type II Diabetes Mellitus,r heumatoid arthritis, haemodialysis-associated amyloidosis, etc.). We set out to find am odel system that would allow for the detailed study of this transformation. The Exenatide variant used here (E5) is protein-like but small (both its chemical synthesis and bacterial expression in af usion system is straightforward);t hus, it can be studied using molecular spectroscopies and modeling methods. Because its folded state is partially helical, its transition toward the amyloid phase results in as ignificant change in secondary structure content, easy and fruitful to monitor by ECD spectroscopy.W ef ound that E5 can be turned into amyloid in ac ontrolled, fully reproducible and tunable manner within al arge range of protein concentrations (80 mM < c prot < 800 mM) at physiologically relevant temperatures.

For efficient targeting of oncogenic K-Ras interaction sites, a mechanistic picture of the Ras-cycle is necessary. Herein, we used NMR relaxation techniques and molecular dynamics simulations to decipher the role of slow dynamics in wild-type and three oncogenic P-loop mutants of K-Ras. Our measurements reveal a dominant two-state conformational exchange on the ms timescale in both GDPand GTP-bound K-Ras. The identified low-populated higher energy state in GDP-loaded K-Ras has a conformation reminiscent of a nucleotide-bound/Mg 2 + -free state characterized by shortened β2/β3-strands and a partially released switch-I region preparing K-Ras for the interaction with the incoming nucleotide exchange factor and subsequent reactivation. By providing insight into mutation-specific differences in K-Ras structural dynamics, our systematic analysis improves our understanding of prolonged K-Ras signaling and may aid the development of allosteric inhibitors targeting nucleotide exchange in K-Ras.

Studying the early phases of amyloid formation is of crucial importance both for understanding the initialization of various pathophysiological processes and for aiding the design of non‐toxic peptide medications that will not become initiators of such processes themselves. This work reports a new monitoring technique using ECD measurements of amyloid progression that can be applied even if the amyloid in question is ThT silent. The amyloid buildup of an Exenatide (in treatment for Type II Diabetes Mellitus) derivate miniprotein (E5) is monitored on a simplified hyperspace, using spectroscopic and molecular modeling techniques. More information can be found in the Full Paper by A. Perczel et al. on page 1968.

Invited for the cover of this issue is the group of András Perczel at Eötvös Loránd University, Budapest, Hungary and colleagues from Osaka University, Japan. The image depicts the amyloid buildup of an Exenatide derivate miniprotein (E5) monitored on a simplified hyperspace. Read the full text of the article at 10.1002/chem.201903826.