Assessing the helical stability of polyXYs at the boundaries of Intrinsically Disordered Regions with MD simulations

Intrinsically disordered regions (IDRs) in proteins lack stable structure. By carrying many hydrophilic and charged residues, it prevents them from forming globular domains and contributes to their flexibility and accessibility. Naturally, regions with reduced amino acid composition (low complexity regions; LCRs) occur within IDRs. Disorder and low complexity in 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 examination of the structural properties of IDRs and the LCRs within, but their inherently dynamic nature requires specific approaches combining sequence analyses, structure predictions and molecular dynamics (MD) simulations. Here, we leverage our previous work where we identified that some types of LCRs combining two residues (polyXY) are frequent within IDRs and confer them with propensity to form helical conformation. We identify a significant accumulation of such polyXYs at the ends of IDRs following alpha-helices that start outside the IDR and may extend through the polyXY into the IDR, particularly from the N-terminal end of the IDR. MD simulations support the dynamic nature of such helical conformations. Our results suggest a mechanism by which evolutionary emergence of LCRs at IDR ends could provide proteins with flexible regions for fold-upon-binding.