Origin of the sequence dependent polyproline II structure in unfolded peptides. Abstract: There are many indications that the unfolded state of polypeptides contains a substantial amount of polyproline type II (P_II) structure. This energetically and structurally distinct state contributes to the thermodynamic pre-organization of the folding search, as well as to the recognition of molecules such as MHC class II antigens and intrinsically unstructured proteins. Using Monte Carlo simulations of natively unfolded peptides in the presence of explicit aqueous solvation under near physiologic conditions, we calculated the conformational propensities of blocked pentapeptides GGXGG (X being any of the amino acids). We observed that residue specific P_II conformational propensity is the result of the modulation of polypeptide backbone hydration by the proximal sidechain, a mechanism unique among protein secondary structures. The calculated conformational propensities should prove useful for the development of a configurational P_II scale necessary for the prediction and design of natural-like polypeptides.