Abstract
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 sim 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 beta -sheet elements. This highlights the potential complexity underlying the energy surface of intrinsically disordered proteins.
Highlights
The exploration of intrinsically disordered proteins in isolation is a crucial step to understand their complex dynamical behavior
Molecular dynamics simulations (MD) data was used to create an Markov State Models (MSMs) based on backboneCα + sidechainO,N self distance matrix that splits the space into 11 different sets of kinetically related conformations referred to as macrostates
MSM subpopulations successfully separate metastable sets of conformations enriched in each secondary structure type (Fig. 1c,d), implying that these structural elements do appear in a concerted way, rather than being the average of residue independent structural propensities
Summary
The exploration of intrinsically disordered proteins in isolation is a crucial step to understand their complex dynamical behavior. Some of the most relevant states feature helical conformations similar to the bound structure of p53 to Mdm[2], as well as novel β-sheet elements This highlights the potential complexity underlying the energy surface of intrinsically disordered proteins. Disordered proteins (IDPs) defy this principle by mediating their biological functions despite lacking a stable three-dimensional s tructure[1,2,3] Such behavior configures a relatively flat energy surface where many isoenergetic conformations c oexist[4]. The energy surface of IDPs if far from being constituted exclusively by random coiled conformations, and pieces of evidence support the existence of partially ordered states[11] The characterization of such partially ordered states is crucial to understand IDPs’ function, their mechanisms of action, and their potential modulation. In terms of aggregated time, the study run for ∼ 10 μs , while others have performed more extensive simulations, ∼ 200 μs but in a single trajectory[19]
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