This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Cadherin molecules form a large family of proteins usually involved in calcium dependent cell-cell adhesion. Some of the cadherin family members, however, directly mediate sensory perception and are essential in vision and hearing. In all cases, calcium binding to highly conserved sites between cadherin repeats is important for function, with impaired calcium binding leading to diseases such as myocardial dystrophy and deafness. In the case of hearing-related cadherins, their elasticity and ability to refold after stretching are also essential for their function under normal and extreme conditions. Here we propose to study cadherin-calcium binding dynamics and cadherin-calcium refolding after stretching with multi-microsecond molecular dynamics simulations. The proposed simulations will shed light on the molecular determinants of cadherin function in hearing, deafness, and beyond.
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