Contrasting solution-state properties within a family of amyloid-binding molecular tools

Abstract

Rational modification to the molecular structure of a family of amyloid-binding bifunctional molecular tools improves their hydrophilicity and aqueous solubility, yet raises questions about self-aggregation. Bifunctional organic molecules enable chemists to design and build molecules that have a wide variety of emergent functional properties. While the majority of these compounds are designed to bind to proteins, this work focuses on those that can bind to amyloid fibrils. These molecular tools can add new functional properties to the fibrils by delivering functional molecular cargo to their surfaces. Second generation tools, which have redesigned amyloid-binding and linker regions, are presented herein. Solubility measurements and partition experiments show that these changes enable the new compounds to dissolve better in pH 7.4 buffered water, which is the natural solvent in which they are most likely to find use and application. One of these compounds, however, contrasts to the others in that it self-associates in DMSO solution. This self-association can be seen experimentally by NMR broadening and fluorescence auto-quenching. An enhanced understanding of how the structural details of these compounds cause this undesired self-association will aid the subsequent development of highly useful amyloid-targeting bifunctional molecules. Herein, several molecular dynamics simulations and DFT geometry optimizations are used to evaluate multiple hypotheses about the nature of the observed self-association.