Assessing the helical stability of polyXYs at the boundaries of intrinsically disordered regions with MD simulations

Intrinsically disordered regions (IDRs) of proteins lack a stable structure. Their high content of hydrophilic and charged residues prevents them from forming globular domains and contributes to their flexibility and accessibility. Naturally, regions with a reduced amino acid composition (low complexity regions; LCRs) are found within IDRs. Disorder and low complexity of protein sequences are linked to various biological functions, including phase separation, regulation, and molecular interactions, and mutations in these regions can contribute to several diseases, including cancer. Understanding these biological properties requires examining the structural properties of IDRs and the LCRs they contain, but their inherently dynamic nature requires specific approaches combining sequence analysis, structure predictions, and molecular dynamics (MD) simulations. Here, we leverage our previous work, where we identified that certain types of LCRs combining two residues (polyXY) are frequent within IDRs and confer them with a propensity to form helical conformations. We identified a significant accumulation of these polyXYs at the ends of IDRs, following alpha helices that begin outside the IDR and can extend through the polyXY into the IDR, particularly from the N-terminal end of the IDR. MD simulations support the dynamic nature of these helical conformations. Our results suggest a mechanism by which the evolutionary emergence of LCRs at IDR ends could provide proteins with flexible regions for fold-upon-binding. • PolyXYs within IDRs facilitate the expansion of helical structures through IDR ends • MD simulations suggest stable helical structures at IDR ends containing polyXYs • Specific polyXYs present a higher helical content within human IDRs