Aggregation of Huntingtin Exon 1 Proteins at Flat and Curved Membrane Surfaces

Huntingtin exon-1 (HTTex1) aggregation at cellular membranes contributes to the propagation of toxic protein assemblies in Huntington’s disease. We explore the thermodynamic and structural mechanisms linking membrane binding, curvature sensing, and nucleation of the aggregates. Here, we use the OpenAWSEM coarse-grained force field code with an effective membrane potential to quantify the folding and surface aggregation behavior of three HTTex1 constructs on both flat lipid bilayers and spherical vesicles. The computed free energy profiles reveal a strong α-helical NT17-mediated affinity (ΔGbind = −9 kcal/mol) and a curvature-dependent enhancement of this binding, with effective enrichments of protein concentration at the membrane surface of approximately 1000-fold for the NT17 by itself, compared to 18-fold for the polyQ-extended constructs NT17-polyQ and 36-fold for NT17-polyQ-polyP. The free-energy aggregation landscapes demonstrate that membrane proximity also enhances the formation of larger oligomers and promotes early oligomerization through N-terminal anchoring. Analyzing curvature-sensation analyses across vesicle radii shows deeper insertion on highly curved surfaces along with stronger binders, consistent with experimental vesicle-binding assays. Our results establish a mechanistic framework for understanding how membranes can act as two-dimensional platforms that both concentrate HTTex1 and template the formation of aggregation nuclei.