Characterization of partially ordered states in the intrinsically disordered N-terminal domain of p53 using millisecond molecular dynamics simulations
The exploration of intrinsically disordered proteins in isolation is a crucial step to understand their complex dynamical behavior. In particular, the emergence of partially ordered states has not been explored in depth. The experimental characterization of such partially ordered states remains elusive due to their transient nature. Molecular dynamics mitigates this limitation thanks to its capability to explore biologically relevant timescales while retaining atomistic resolution. Here, millisecond unbiased molecular dynamics simulations were performed in the exemplar N-terminal region of p53. In combination with state-of-the-art Markov state models, simulations revealed the existence of several partially ordered states accounting for [Formula: see text] 40% of the equilibrium population. Some of the most relevant states feature helical conformations similar to the bound structure of p53 to Mdm2, as well as novel [Formula: see text]-sheet elements. This highlights the potential complexity underlying the energy surface of intrinsically disordered proteins. ; The authors thank volunteers at GPUGRID.net for contributing with computational resources and Acellera for funding. G.D.F. acknowledges support from MINECO (Unidad de Excelencia María de Maeztu MDM-2014-0370 and BIO2017-82628-P) and FEDER. This project received funding from the European Union's Horizon 2020 Research and Innovation Programme under Grant Agreement 823712 (CompBioMed2 Project).