Joe Passman, University of Utah
Life Sciences
Neurodegenerative disorders and amyloidosis are thought to be a consequence of the misfolding of intrinsically disordered proteins (IDPs). In non-pathogenic states, IDPs are thought to manipulate their configurational ensembles (CEs) – through partially folding and/or forming secondary structure – to create binding sites for the multiple interaction partners necessary for cell-signaling, recognition, and regulation. An obstacle to accurate in vivo understanding of non-pathogenic mechanisms is that little is known about the impact of the crowded cellular environment on the global (i.e. partial folding) and local structural characteristics (i.e. secondary structure) of IDPs. It is difficult to understand why an IDP may misfold if little atomistic structural understanding exists regarding IDP functional mechanisms in non-adherent physiological states.
In order to test the hypothesis that IDPs become more globally compact and locally form a larger proportion of helical secondary structure at interaction sites upon crowding, 1 µs of aggregate atomistic molecular dynamics (MD) simulation and enhanced molecular dynamics simulation was performed on the non-crowded 107 residue λ N model IDP. MD data were compared with NMR data from recent work on the λ N protein. The ensemble radius of gyration, a measure of global protein structural order, decreased during MD. Contrary to the hypothesis regarding local structural properties of IDPs, we found that the β-strand content at interaction sites is enhanced relative to other residues along the sequence during 1 µs of aggregate MD simulation. Future work will investigate the impact of macromolecular crowding on IDP CEs to more accurately model in vivo IDP biophysical mechanisms.