Coarse Grained Modeling of Intrinsically Disordered Protein Structures and Dynamics

Contrary to natively folded proteins, which often have a single stable 3D structure, Intrinsically Disordered Protein (IDP) structures dynamically fluctuate between many conformations. This complexity impedes their study and the understanding of their functions. Experimental techniques can probe aspects of the conformations, but often different techniques or conditions offer seemingly contradictory results. In this thesis, I use coarse-grained models and simulations to investigate the structures and dynamics of IDPs. One system I focus on is the Nuclear Pore Complex (NPC): a bidirectional selective gate for cargo traveling across the nuclear envelope of eukaryotic cells. A key functional component of the NPC is the layer of intrinsically disordered FG nucleoporins attached to the interior of the transport channel. Elucidating the mechanism of transport remains elusive due to the size and complexity of the NPC, but will contribute to the understanding of diseases associated with mutations in the NPC, viruses which enter the nucleus via the NPC, and drug delivery into the nucleus, as well as the development of NPC inspired devices for nanotechnological applications. I show how a mean field model for surface grafted FG nups reconciles several conflicting experimental observations and theories of transport. Due to a lack of unique structure, the influence of the amino acid sequence on IDP structures and dynamics is unclear. Various evidence points to the overall importance of general properties of the sequence rather than the atomistic details of the amino acids. Using coarse-grained simulations, I investigate how the effects of several key sequence properties on the polymer dimensions and end-to-end distance dynamics of IDPs. These results have implications for interpreting experimental measurements as well as developing appropriate models of IDPs.Ph.D