Intrinsically disordered proteins (IDPs) are frequently involved in human diseases including cancers and neurodegenerative diseases. The heterogeneous and dynamic nature of these proteins is a major challenge for both structural characterization and targeting with small molecules. With the recent development of efficient enhanced sampling approaches, rebalanced protein force fields, and GPU-accelerated computing, molecular dynamics (MD) simulations can now provide a viable tool to characterize the disordered ensembles of IDPs and examine how they may be modulated by disease-associated mutations and small molecules. We will discuss two of our recent case studies on the transactivation domain of tumor suppressor p53 and Amyloid-beta42 peptide. The results suggest that induced conformational collapse of IDPs through nonspecific interactions may be a general mechanism for shielding key sites to inhibit recognition of their targets or aggregation.

Targeting intrinsically disordered proteins via nonspecific binding

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.