Sequence-Dependent Backbone Dynamics and Membrane Association of Intrinsically Disordered Proteins

Intrinsically disordered proteins (IDPs) account for a significant fraction of any proteome and are central to numerous cellular functions. Yet how sequences of IDPs code for their conformational ensembles, conformational dynamics, and ultimately, functions is poorly understood. I will report advances from our computational and experimental studies of ChiZ, a membrane protein that contains an intrinsically disordered N-terminal region (NT) and is a component of the cell division machinery in Mycobacterium tuberculosis. NMR data revealed non-uniform backbone dynamics along the sequence of the 64-residue NT [1]. Molecular dynamics (MD) simulations traced the origin to correlated segments, which are stabilized by polyproline II stretches, salt bridges, cation-p interactions, and sidechain-backbone hydrogen bonds. Moreover, the extent of segmental correlation is sequence-dependent: segments (in particular, in the N-half; e.g., residues 11-29) where internal interactions are more prevalent manifest elevated supra-ns “collective” motions and suppressed local motions on the sub-ns timescales. NMR experiments found that NT associates with acidic membranes, but most residues remain dynamic, exception for a subset of Arg residues [2]. MD simulations provided crucial details on the fuzzy conformational ensemble, showing NT anchored to membranes in the midsection, in particular by Arg37. Anionic residues, all the N-half, compete with acid membranes for interacting with Arg residues. Consequently C-half Arg residues have higher propensities to interact with the membrane. This asymmetry between N-half and C-half in membrane interaction is accentuated when NT is tethered to the membrane via the adjacent transmembrane helix. These findings serve as paradigms for sequence-conformation-dynamics-function relations of IDPs.