Insight into the Structure of the “Unstructured” Tau Protein

Combining structural proteomics experimental data with computational methods is a powerful tool for protein structure prediction. Here, we apply a recently developed approach for de novo protein structure determination based on the incorporation of short-distance crosslinking data as constraints in discrete molecular dynamics simulations (CL-DMD), for the determination of the conformational ensemble of tau protein in solution. The predicted structures were in agreement with surface modification and long-distance crosslinking data. Tau in solution was found as an ensemble of rather compact globular conformations with distinct topology, inter-residue contacts, and a number of transient secondary-structure elements. Regions important for pathological aggregation consistently were found to contain β strands. The determined structures are compatible with the tau protein in solution being a molten globule at near-ground state with persistent residual structural features which we were able to capture by CL-DMD. The predicted structure may facilitate an understanding of the misfolding and oligomerization pathways of the tau protein. [Display omitted] •441-residue tau protein structure was solved by all-atom DMD simulations•Structural proteomics experimental data were used in protein structure prediction•Tau is a rather compact conformational ensemble with distinct subdomain topology•Extensive β sheet structure was detected in the aggregation-prone R1-R4 repeat regions Short-distance crosslinking constraint-guided all-atom discrete molecular dynamics simulations (CL-DMD) was used to predict the conformational ensemble of the full-length tau protein in solution. Tau in solution was found to be a fairly compact globular protein that contains persistent structural features in the regions important for pathological aggregation.