Structural ensemble determination of intrinsically disordered protein, NUPR1, by replica-exchange molecular dynamics simulation

Nuclear Protein 1 (NUPR1) is a transcription regulator and is involved in various diseases, including cardiovascular disease, inflammatory response, and cancer. NUPR1, 82 amino acid residue, is an intrinsically disordered protein (IDP), which is known to have no stable secondary and tertiary structure. NMR or SAXS can characterize the solution structure and dynamics of IDPs, but the ensemble structures revealed by those experimental techniques are rare and are not high-resolution structures.

In this study, we report the configurational ensembles of NUPR1 employing all-atom molecular dynamics simulation with a replica-exchange method. In particular, CHARMM36m and a99SB-disp, well-known and validated force fields for IDP, were employed. To check the convergence of our simulation, we started the simulation from different initial conformation, one from extended and another from folded (highly helical state). In addition, we performed the simulation using the initial conformation from Alphafold’s predicted structure.

For the analysis of trajectories, we estimated a radius of gyration (Rg) for structural compactness and residue helicity for dynamically generated conformations. We estimated the ensemble-averaged theoretical SAXS data and compared it with experimental data to check the accuracy of our simulation.

This study predicts the configurational ensemble of NUPR1. Our simulation and analysis can be applied to other IDPs and provide a clue to screening of IDP-targeting drugs.