PT  - JOURNAL ARTICLE
AU  - Sedlak, Steffen M.
AU  - Schendel, Leonard C.
AU  - Gaub, Hermann E.
AU  - Bernardi, Rafael C.
TI  - Streptavidin/biotin: Tethering geometry defines unbinding mechanics
AID  - 10.1126/sciadv.aay5999
DP  - 2020 Mar 01
TA  - Science Advances
PG  - eaay5999
VI  - 6
IP  - 13
4099  - http://advances.sciencemag.org/content/6/13/eaay5999.short
4100  - http://advances.sciencemag.org/content/6/13/eaay5999.full
SO  - Sci Adv2020 Mar 01; 6
AB  - Macromolecules tend to respond to applied forces in many different ways. Chemistry at high shear forces can be intriguing, with relatively soft bonds becoming very stiff in specific force-loading geometries. Largely used in bionanotechnology, an important case is the streptavidin (SA)/biotin interaction. Although SA’s four subunits have the same affinity, we find that the forces required to break the SA/biotin bond depend strongly on the attachment geometry. With AFM-based single-molecule force spectroscopy (SMFS), we measured unbinding forces of biotin from different SA subunits to range from 100 to more than 400 pN. Using a wide-sampling approach, we carried out hundreds of all-atom steered molecular dynamics (SMD) simulations for the entire system, including molecular linkers. Our strategy revealed the molecular mechanism that causes a fourfold difference in mechanical stability: Certain force-loading geometries induce conformational changes in SA’s binding pocket lowering the energy barrier, which biotin has to overcome to escape the pocket.