Understanding the conformational dynamics of an intrinsically disordered protein bound to a small molecule

Intrinsically disordered proteins (IDPs) have been implicated in a wide range of human diseases. Due to their intrinsic conformational variability, IDPs are generally not effective for conventional structure-based drug design. Recently, ZZW-115 has been identified as a promising inhibitor of NUPR1 (an IDP whose overexpression is involved in various cancers), offering a potential lead for the development of novel cancer therapies. Understanding the conformational dynamics is crucial for comprehending the inhibitory action of ZZW-115, revealing the binding modes and dynamic interactions between ZZW-115 and NUPR1. Here, we present a computational study employing atomic-level Molecular dynamics (MD) simulations coupled with Umbrella sampling (US) to investigate the binding of ZZW-115 to NUPR1, elucidating the conformational changes and dynamics involved in the interaction. The Potential of Mean Force (PMF) plot showed a minimum value of 9Å at NUPR1-ZZW-115 separation with a dissociation energy of 2 kcal/mol. From Root Mean Square Deviation (RMSD) and secondary structure analysis, the conformational dynamics of NUPR1 was found to be varied as a function of its centre of mass (CoM) distance from ZZW-115. The NUPR1-ZZW-115 complex with the lowest potential energy extracted from the PMF plot was used to study the conformational dynamics of NUPR1 in unbound and complex form. The study reveals specific residues and binding pockets in NUPR1's disordered region that bind to ZZW-115, providing valuable insights into its inhibitory mechanism, enabling the development of effective drug design for therapeutic purposes.