Ligand Binding on Intrinsic Disordered Proteins: Focus on Human Alpha-Synuclein

Intrinsically disordered proteins (IDPs) are involved in a wide variety of human diseases (1). Hence, interfering with the function of IDP-disease-associated proteins offers a highly attractive objective for drug development (2). Unfortunately, rational approaches have been hampered so far because of variety of problems absent in traditional drug design protocols. These issues include the highly dynamic nature of IDPs (3), the presence of local and long-range conformational rearrangements (4), transient secondary structure, transient long-range tertiary structure (5, 6).Here we present a combined NMR/molecular dynamics protocol that provides quantitative information on ligand poses to IDPs. The approach is based on a geometrical-based analysis of MD trajectory with a flexibility index able to detect conformational transition of residues' backbone (Caliandro, C, Rossetti, G, Carloni, P, 2012 JCTC in press). The protocol is applied on dopamine in complex with the naturally unfolded protein human α-synuclein. The proposed protocol is very general and it could be used to investigate the pose of novel molecules binding to any IDP