Disorder serves a functional role in cellular membranes and flexible protein domains. An in-plane fluid mixture of phospholipids, carbohydrates, membrane proteins, and more constitute the plasma membrane. Disordered regions of proteins leverage a wide conformational space to facilitate complexation, signaling, and regulatory interactions. Experimental approaches which quantify structural information of these systems ideally facilitate biomimetic sample environments. Scattering techniques provide a minimally restrictive platform for characterizing macromolecular systems including lipid bilayers and intrinsically disordered proteins. This thesis contains studies of these systems which utilize X-ray and neutron scattering methods complemented by computational and theoretical structural predictions.

The small GTPase KRas acts as a binary switch at the plasma membrane, anchored by a flexible domain, participating in signaling pathways vital for cellular survival and proliferation. Its localization to the plasma membrane is dependent on chaperone proteins, such as SmgGDS, which bind and traffic it through the cytosol. Two isoforms of SmgGDS regulate the prenylation and localization of small GTPases: SmgGDS-607 binds unprenylated small GTPases while SmgGDS-558 associates and houses the lipid anchor of prenylated small GTPases in a hydrophobic pocket. Structural and thermodynamic details of KRas complexation with SmgGDS are critical for understanding Ras biology and for identifying potential targets for chemical inhibition of oncogenic KRas signaling. We show that SmgGDS-558 readily solubilizes KRas bound to anionic membranes with a binding affinity larger than that of KRas associating with the membrane. Using a combination of solution scattering and molecular dynamics simulations, a configurational ensemble of a flexible SmgGDS-558/KRas complex was determined in which specific interactions were found to be limited to the C-terminal end of the hypervariable region. Informed by mutational studies which identify a collection of SmgGDS residues as important for binding KRas, we observe a set of anionic residues near the hydrophobic pocket of SmgGDS-558 directly associating KRas within the determined flexible ensemble.