Predicted condensation-related signatures localize to two C-terminal regions of the prion protein across cervid PRNP variants associated with chronic wasting disease

Abstract

Genetic variation in cervid PRNP influences chronic wasting disease (CWD) susceptibility and progression, but it remains unclear whether disease-associated substitutions produce localized differences in sequence-derived properties relevant to prion protein (PrPC) condensation. We compared a white-tailed deer (WTD) reference sequence with 10 modeled variants on the same mature PrP scaffold (residues 24-233). For each sequence, we calculated intrinsic disorder, FuzDrop per-residue droplet-promoting propensity (pDP) and binding-mode entropy (Sbind), predicted residue-level pKa values, and a discrete-charge summary at pH 7.0. The overall profiles preserve a long N-terminal droplet-promoting region, whereas variant-associated differences are concentrated in selected intervals. In the FuzDrop outputs, residues 126-140 show allele-dependent changes in pDP near the droplet-promoting threshold, and residues 220-230 show variant-specific changes in Sbind, including lower Sbind for S225F/Y and higher Sbind for elk-like Q226E. These differences occur without large changes in overall intrinsic disorder. KaML pKa predictions identify near-neutral titratable sites that provide electrostatic context for these local predictor differences. Independent atomistic simulations of monomeric PrP further detected variant-sensitive backbone behavior and intramolecular contacts involving these intervals. Together, the analysis identifies residues 126-140 and 220-230 as computationally defined candidate intervals that overlap regions implicated independently in prion conversion or CWD fibril structure, motivating direct tests of cervid PrP condensation and maturation.