Short Arginine-Based Peptides As Predictors for the Extended Structure of Polyarginine Sequences in Intrinsically Disordered Proteins

Abstract

Intrinsically disordered proteins (IDPs) and regions (IDRs) are often rich with charged amino acids. During important biological processes, protein-biomolecule interactions are often driven by one or more charged residues within an IDR. Several lines of experimental and computational evidence suggest that polypeptides and proteins that carry high net charges tend to adopt extended conformations. Furthermore, the average end to end distances often exceed expectations for self-avoiding random coils. Here, we show that charged arginine (R) residues in even short glycine (G) capped model peptides (GRRG and GRRRG) significantly affect the conformational propensities of each other when compared to the intrinsic propensities of a mostly unperturbed arginine in the tripeptide GRG. A conformational analysis based on experimentally determined J-coupling constants from heteronuclear NMR spectroscopy and amide I’ band profiles from polarized Raman spectroscopy reveals that nearest neighbor interactions stabilize extended β-strand conformations at the expense of polyproline II and turn conformations. The results from MD simulations with an CHARMM36m force field and TIP3P water reproduce our results only to a limited extent. The use of the Ramachandran distribution of the central residue of GRRRG in a calculation of end-to-end distances of polyarginines of different length yielded the expected power law behavior. The scaling coefficient of 0.66 suggests that such peptides would be more extended than predicted by a self-avoiding random walk.