Simulated Forced Unbinding of Clustered Protocadherins

Clustered protocadherins belong to the cadherin superfamily of adhesion proteins and are involved in neuronal connectivity and self-recognition. Clustered protocadherins have six extracellular cadherin (EC) repeats with about 100 residues each. Recent crystallographic structures suggest an antiparallel homophilic binding interface that involves overlapped EC1 to EC4 repeats. Here, we present steered molecular dynamics simulations of α, β, and γ clustered protocadherins homodimers exploring the forced unbinding of their adhesive interface. Constant velocity stretching simulations were performed on these homodimers at 10 nm/s, 1 nm/ns, 0.5 nm/ns, and 0.1 nm/ns. All protocadherins show some unfolding at the highest stretching speed, whereas simulations at slower speeds revealed unbinding pathways for the complex without unfolding. Force-extension profiles show broad force peaks that reflect the extended antiparallel interface of protocadherins, as well as the formation of transient interactions between protomers that break during unbinding. The unbinding pathways observed in simulations may help further elucidate the molecular basis of protocadherin binding specificity.