1. Molecular biomechanics

""

The response of proteins to non-equilibrium ​mechanical force is fundamentally important for many processes in biology, including muscle contraction, hearing, cell adhesion, and bacterial pathogenesis. If we consider protein-protein interactions, for example, we know that the amount of mechanical force that a protein complex can resist before breakage can be decorrelated from its thermodynamic affinity. Using biophysical tools such as the atomic force microscope (AFM), we study molecular complexes that, when mechanically stressed, dissociate along energetic pathways that are inaccessible under purely thermal excitation. These properties lead to diverse mechano-responsive behaviors in biology, such as force-activated catch bonds, shear-induced blood coagulation​, and enhanced pathogenic adhesion under flow.

Using single-molecule force spectroscopy (AFM-SMFS), we quantify the resistance of individual molecules and molecular complexes to applied forces. We use this technique to study protein folding/unfolding transitions, and rupture of receptor-ligand complexes under force. The aim is to understand how mechanostable adhesion proteins perform their intended functions at the molecular level. Through these experiments we seek to understand what makes protein interactions mechanically strong, or weak, and to incorporate this information into the design and engineering of biological materials.

2. Bio-inspired polymerization

""

© M. Oeggerli/Micronaut 2018, supported by Pathology, University Hospital Basel, C-CINA, Biozentrum, University of Basel.

Modification of cell surfaces with synthetic hydrogels is a promising approach from controlling cell behavior. We are currently developing genetically controlled systems that enable cells to auto-encapsulate themselves inside cytoprotective hydrogel capsules. The image shows an encapsulated budding yeast cell directly adjacent to a non-encapsulated one. This system links inducible gene expression with rapid formation of a synthetic hydrogel capsule that protects target cells against osmotic lysis and mediates communication with the extracellular space through a tunable and permeable hydrogel capsule. In enzyme-mediated polymerization systems, several naturally occurring enzymes can be utilized for polymerization/cross-linking of synthetic compounds. We are pursuing enzyme-mediated and affinity protein-mediated polymerization as a method for interfacing synthetic polymers/hydrogels with cells. Our goal is to develop synthetic biological systems that are capable of initiating polymerization, and of being used as a readout for high-stability or accelerated enzyme phenotypes. We envision application of these systems in cell screening, disease diagnosis, tissue engineering, and for the ultrahigh throughput directed evolution of therapeutic enzymes.

3. Smart polymers and proteins

""

Stimuli-responsive or ‘smart’ polymers undergo dramatic conformational changes in response to slight changes in environmental conditions. Examples include small changes in pH, temperature, salt, and light that give rise to collapse or expansion of polymer chains in aqueous media. These environmentally responsive materials act as nanoscale signal transducers, or molecular amplifiers that sense their surroundings and respond with an output signal. We work with both synthetic polymers and elastin-like polypeptides (i.e. repetitive protein polymers) possessing ‘smart’ properties. Here we are interested in integrating smart materials into synthetic molecular systems to control biomolecular activity in a predictable way, for example, by modulating surface adhesion and friction, by controlling biological activity (e.g., enzymatic activity), or by directing nanoparticle self-assembly.