Hidden Order in an Intrinsically Disordered Protein Region

Previously, we presented evidence of glassy dynamics in a model intrinsically disordered protein region (IDR) system, suggesting that it contains hidden regions of order. This model system is a polyprotein derived from the disordered neurofilament light tail (NFLt) domain, which is part of a large group of IDRs in the neuronal cytoskeleton that are responsible for the structure and mechanics of the axon. Using magnetic tweezers, we showed that NFLt polyproteins exhibit a slow extension change over time, in response to a change in applied tension. These extension changes exhibit a nonexponential (often logarithmic) time dependence and are history-dependent, two characteristic features of a glassy system. Here, we use a combination of coarse-grained molecular dynamics simulations and experimental data on the NFLt polyproteins to determine the microscopic origin of the glassy dynamics. We establish which residues form the hidden ordered regions and develop a model based on these residues that can recapitulate the polyprotein’s glassy behavior. Based on their associated sequence properties, we suspect that hidden ordered regions and glassy behavior are likely to apply broadly to other IDRs found throughout the cellular cytoskeleton.