Keynote Talk  - Wednesday, 15 September I 10:05 AM (CEST)

Mechanical anisotropy is a general property of biomolecules that manifests when mechanical forces are applied from different directions. Due to its vectorial nature, mechanical force always has not only a magnitude but also an associated direction, and molecular deformation is significantly modulated by the anchoring positions through which forces are applied. This talk will focus on recent work in the Nash Lab optimizing molecular pulling geometries of biotherapeutics. We report a new AFM measurement setup and bioorthogonal protein engineering workflow[1] that allows us to apply tension to non-antibody therapeutic binding scaffolds through controlled anchor points at the N-terminus, C-terminus or at internal sequence positions. This method has revealed that dissociating complexes by pulling from internal sequence positions significantly increases the unbinding forces. Anchor point optimization can be considered a new paradigm for improving binding strength of therapeutic scaffolds that does not require mutagenesis of binding paratopes, with implications for the design of drug delivery systems optimized to work under shear flow. 

 

References: 

[1] Liu, Z.; Moreira, R. A.; Dujmović, A.; Liu, H.; Yang, B.; Poma, A. B.; Nash, M. A. Optimizing Mechanostable Anchor Points of Engineered Lipocalin in Complex with CTLA-4. Bioarxiv, 2021, 2021.03.09.434559. https://doi.org/10.1101/2021.03.09.434559.