Poster abstracts
Poster number 56 submitted by Carter Wheat
Elastic properties of the inner-ear tip link explored using all-atom molecular dynamics simulations
Carter Wheat (Chemistry and Biochemistry, The Ohio State Biochemistry program), Jasanvir Sandhu, Elakkiya Tamilselvan, Yoshie Narui, Pedo De-la-Torre, Joseph Sudar, Travis Harrison-Rawn, Marrisa Boyer, Anee Ashraf, Daisy Alvarado, Marcos Sotomayor
Abstract:
Vertebrate sound and balance perception relies on mechanoelectrical transduction, or the transformation of mechanical sensory information from sound waves and head movements into electrochemical signals to be interpreted by the brain. Inner-ear hair cells are specialized sensory cells that detect mechanical vibrations when their apical stereocilia shear upon pressure wave propagation. Movement of the stereocilia stretches an attached filamentous protein complex termed the tip link, which mechanically gates an ion channel for hair cell depolarization to signal through their basal synapse. The tip link is formed by the interactions of protocadherin-15 (PCDH15) and cadherin-23 (CDH23), which adopt a heterotetrameric assembly in vivo. Owing to the massive size of the tip link complex (~ 1 MDa) and hair cell fragility, studying the elastic properties of the tip link experimentally has been very challenging. With the use of existing x-ray crystal structures combined with AlphaFold2 structure predictions of the CDH23 and PCDH15 ectodomains, we constructed an atomistic model of the tip link for in silico force application. Here, we present all-atom steered MD simulations of the inner-ear tip link, and report force measurements and important structural properties of their interactions upon application of shearing force. We observe that extracellular cadherin repeats (EC) with non-canonical linker sequences can impart conformational variability to the tip link by introducing kinks to the filament. We also observe that non-EC repeats in PCDH15 and CDH23 provide elasticity by first unrolling before full extension upon force application. With these simulations, we address previously uncharacterized structural dynamics of the tip link under tension at the atomistic level and better postulate how deafness causing mutations in PCDH15 and CDH23 mechanistically affect the tip link function.
Keywords: Molecular dynamics, mechanosensation , hearing