Intrinsically Disordered Regions May Lower the Hydration Free Energy in Proteins: A Case Study of Nudix Hydrolase in the Bacterium Deinococcus radiodurans

The proteome of the radiation- and desiccation-resistant bacterium D. radiodurans features a group of proteins that contain significant intrinsically disordered regions that are not present in non-extremophile homologues. Interestingly, this group includes a number of housekeeping and repair proteins such as DNA polymerase III, nudix hydrolase and rotamase. Here, we focus on a member of the nudix hydrolase family from D. radiodurans possessing low-complexity N- and C-terminal tails, which exhibit sequence signatures of intrinsic disorder and have unknown function. The enzyme catalyzes the hydrolysis of oxidatively damaged and mutagenic nucleotides, and it is thought to play an important role in D. radiodurans during the recovery phase after exposure to ionizing radiation or desiccation. We use molecular dynamics simulations to study the dynamics of the protein, and study its hydration free energy using the GB/SA formalism. We show that the presence of disordered tails significantly decreases the hydration free energy of the whole protein. We hypothesize that the tails increase the chances of the protein to be located in the remaining water patches in the desiccated cell, where it is protected from the desiccation effects and can function normally. We extrapolate this to other intrinsically disordered regions in proteins, and propose a novel function for them: intrinsically disordered regions increase the “surface-properties” of the folded domains they are attached to, making them on the whole more hydrophilic and potentially influencing, in this way, their localization and cellular activity. Intrinsically disordered proteins and protein segments carry out a wide range of important biological functions despite their lack of permanent tertiary structure. Using advanced computational methods we study the biophysical properties of the intrinsically disordered regions in the enzyme nudix hydrolase from the desiccation- and radiation-resistant bacterium D. radiodurans. Interestingly, these regions are absent in homologue proteins in non-extremophile bacteria, suggesting that they might be involved in helping the key rescue-and-repair proteins in D. radiodurans, such as nudix hydrolase, adapt to the extreme absence of water. We show that the disordered regions in nudix hydrolase enlarge the overall surface of the enzyme, and most importantly, increase its overall affinity for water (i.e. its hydrophilicity). We suggest a novel hypothesis that this, indeed, may be the principal function of disordered regions in some cases: they increase the chances of the protein to be located in the remaining water patches in the desiccated cell, where it is protected from the desiccation effects and can function normally.