How ARVC-Related Mutations Destabilize Desmoplakin: An MD Study

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial heart disease linked to mutations in several desmosomal proteins, but the specific effects of these mutations on the molecular level are poorly understood. Among the many documented ARVC-related genetic variants, a striking hotspot of nine mutations has been identified in the plakin domain of desmoplakin. This hotspot can be found at the meeting point of three different subdomains of desmoplakin: two spectrin repeats and a Src homology 3 domain. We set out to understand the effect of these mutations. We determine, using molecular dynamics simulations, how these mutations affect the mechanics of this interface, performing two different classes of simulations. First, we sample the dynamics of the plakin domain, in particular the tendency of the interdomain hinge to buckle, and then we apply an external force onto the constructs and determine the force necessary to break them. We find that surface-exposed mutations are not affecting the dynamics to a very large degree but that most buried mutations make the junction more flexible and decrease the rupture forces observed. Our data suggest that buried ARVC mutations destabilize desmoplakin and thereby impair desmosome integrity under tension.