Towards the design and development of peptidomimetic inhibitors of the Ataxin-1 aggregation pathway

Spinocerebellar Ataxia Type 1 is a degenerative disorder caused by polyglutamine expansions and aggregation of Ataxin-1. The interaction between Capicua (CIC) and the AXH domain of Ataxin-1 protein has been suggested as a possible driver of aggregation for the expanded Ataxin-1 protein and the subsequent onset of Spinocerebellar ataxia 1. Experimental studies have demonstrated that short constructs of CIC may prevent such aggregation and suggested this as a possible candidate to inspire the rational design of peptidomimetics. In this work, molecular modelling techniques, namely the Alchemical mutation and forcefield-based molecular dynamics, have been employed to propose a pipeline for the rational design of a CIC-inspired inhibitor of the ataxin-1 aggregation pathway. In particular, this study has shown that the Alchemical mutation can estimate the affinity between AXH and CIC with good correlation with experimental data, while molecular dynamics shed light on molecular mechanisms that occur for stabilization of the interaction between the CIC-inspired construct and the AXH domain of Ataxin-1. This work lays the foundation for a rational methodology for the in-silico screening and design of peptidomimetics, which can expedite and streamline experimental studies to identify strategies for inhibiting the ataxin-1 aggregation pathway.