The ribonucleoprotein hnRNPA1 mediates binding to RNA and DNA telomeric G-quadruplexes through an RGG-rich region.

hnRNPA1, a protein from the heterogeneous-nuclear ribonucleoprotein family, mediates cellular processes such as RNA metabolism and DNA telomere maintenance. Besides the folded RNA recognition motifs, hnRNPA1 has a ∼135 amino-acids long low-complexity domain (LCD) consisting of an RGG-rich region and a prion-like domain (PrLD). Biochemical data suggest that the RGG-rich region modulates the recognition of G-quadruplexes (GQs) in the telomeric repeats. Here, we utilize an in-house developed replica exchange technique (REHT) to generate the heterogeneous conformational ensemble of hnRNPA1-RGG and explore its functional significance in telomere maintenance. Single chain statistics and abundance of structural motifs, as well as consistency with experimentally reported structural data suggest faithful recapitulation of local interactions. We also introduce a protocol to generate functionally significant IDP-nucleic acid complex structures that corroborate well with the experimental knowledge of their binding. We find that RGG-box preferentially binds to the grooves and loops of GQs providing specificity towards certain GQ structures with its sequence and secondary structures. Turn-like structures expose Phe and promote stacking with the G-tetrads, while Tyr and Asn residues form essential hydrogen bonds and electrostatic interactions. Several of these residues were also identified as important by the earlier reported HSQC chemical shift data. Our binding and simulation studies also reveal that a minor population of the RGG-box can perturb telomeric GQs structure, which likely expedites the unfolding activities of hnRNPA1-UP1 at the telomeric end.