Exploiting the intrinsic structural dynamics of biomolecules as design feature - from antimicrobials to novel biosensors
Hans-Joachim Wieden1, Dustin Smith1,2, Davinder Kaur Dhalla1,2
1University of Manitoba, Winnipeg, Canada,
2University of Lethbridge, Lethbridge, Canada
The ability of biomolecules to respond to a wide range of input signals is essential for life. Molecular switching and recognition events are critical for the cellular machinery regulating essential biological processes. Molecular switches are therefore of great interest for synthetic biology, biomedical, and protein engineering applications. In contrast to their fundamental role, a detailed understanding of the design principles and biophysical parameters underlying their switching-mechanism is lacking. We have developed a combined experimental biophysics and computational analysis platform that allows us to investigate the role of intrinsic structural dynamics changes for biomolecular decision making and identified these properties as a previously overlooked contributor to antibiotic action (Girodat,[...], Wieden, JACS 2019; Girodat, [...], Wieden, JMB 2020) or as a parameter for the rational design of biomolecular devices including custom biosensors (Smith,[...],Wieden, Biosens Bioelectron 2022; Smith,[...],Wieden, Sensors 2022).
Here we report a Molecular Dynamics (MD) guided study revealing for the first time how the Human cytomegalovirus (HCMV) pentamer exploits the intrinsic structural dynamics of host Neuropilin 2 (Nrp2) to gain access into the host cell (Dhalla, Smith & Wieden 2022, PNAS under review). We provide an overview of how computer aided description of structural dynamics and their underlying biophysical properties can be matched with experimental strategies such as single molecule FRET (Morse,[...],Wieden, PNAS 2020) and rapid kinetics to provide a multiscale description of switching and biomolecular recognition events in a wide range of biological systems.