Across (conformational) space and (relaxation) time: using coarse-grain simulations to probe the intra- and interdomain dynamics of the Tau protein

The biological importance of intrinsically disordered proteins (IDP) has been established for over two decades, yet these systems remain difficult to characterize, as they are better described by conformational ensembles instead of a single reference structure for their folded counterparts. Tau is a prominent member of the IDP family which sees its cellular function regulated by multiple phosphorylations sites, and whose hyperphosphorylation is involved in neurodegenerative diseases such as Alzheimers. We use coarse-grain MD simulations with the CALVADOS model to investigate the conformational landscape of tau without and with phosphorylations. Characterizing the local compactness of IDPs allows us to highlight how disorder comes in various flavors, as we can define different domains along the tau sequence. We define the IDPs Statistical Tertiary Organization (STO) as the average spatial arrangements of domains, which constitutes an extension of the tertiary structure of folded proteins. We also use IDP specific metrics to characterize the local curvature and flexibility of tau. Comparing the local flexibilities with T2 relaxation times from NMR experiments, we show how this metric is related to the protein dynamics. A curvature and flexibility pattern in the repeat domains can also be connected to tau binding properties, without having to explicitly model the proteins interaction partner. Finally, we rediscuss the original paperclip model that describes the spatial organization of tau, and how phosphorylations impact it. The resulting changes in the protein intra- and interdomain interaction pattern allow us to propose experimental setups to test our hypothesis. TOC graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/665865v3_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@7b7fc5org.highwire.dtl.DTLVardef@182a9org.highwire.dtl.DTLVardef@129515borg.highwire.dtl.DTLVardef@19c6d8f_HPS_FORMAT_FIGEXP M_FIG C_FIG