Intrinsically Disordered Proteins Can Behave as Different Polymers across Their Conformational Ensemble

Intrinsically disordered proteins (IDPs) are macromolecules, which in contrast to well-folded proteins explore a large number of conformationally heterogeneous states. In this work, we investigate the conformational space of the disordered protein β-casein using Hamiltonian replica exchange atomistic molecular dynamics (MD) simulations in explicit water. The energy landscape contains a global minimum along with two shallow funnels. Employing static polymeric scaling laws separately for individual funnels, we find that they cannot be described by the same polymeric scaling exponent. Around the global minimum, the conformations are globular, whereas in the vicinity of local minima, we recover coil-like scaling. To elucidate the implications of structural diversity on equilibrium dynamics, we initiated standard MD simulations in the <i>NVT</i> ensemble with representative conformations from each funnel. Global and internal motions for different classes of trajectories show heterogeneous dynamics with globule to coil-like signatures. Thus, IDPs can behave as entirely different polymers in different regions of the conformational space.