The unfolded state and flexible linkers in the folded structure play essential roles in protein stability and folding and protein-protein interactions. Intrinsic to these roles is the fact that unfolded proteins and flexible linkers sample many different conformations. Polymer models may capture this and complement experiments in elucidating the contributions of the unfolded state and flexible linkers. Here I review what can be predicted from these models and how well these predictions match

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... eriments. For example, Gaussian chain models give quantitatively reasonable predictions of the effects of residual chargecharge interactions in the unfolded state and qualitatively reasonable results for the effects of spatial confinement and macromolecular crowding on protein stability. A wormlike chain model has met with success in quantifying the effects of flexible linkers in binding affinity enhancement and in regulatory switches. In future developments, more realistic models may emerge from molecular dynamics simulations, and these models will guide experiments to advance our understanding of the unfolded state and flexible linkers. . 1 Abbreviations: NMR, nuclear magnetic resonance; BPTI, bovine pancreatic trypsin inhibitor; FnFn3(10), tenth fibronectin type III domain of human fibronectin; drk-SH3, N-terminal SH3 domain of drk; DnaB-(24-136), residues 24-136 of the N-terminal domain of DnaB; RPA70AB, central region of the 70 kDa subunit of replication protein A; HEL, hen egg white lysozyme.