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Abstract
Many of the proteins involved in key cellular regulatory events contain extensive intrinsically disordered regions that are not readily amenable to conventional structure/function dissection. The oncoprotein c-MYC plays a key role in controlling cell proliferation and apoptosis and more than 70% of the primary sequence is disordered. Computational approaches that shed light on the range of secondary and tertiary structural conformations therefore provide the only realistic chance to study such proteins. Here, we describe the results of several tests of force fields and water models employed in molecular dynamics simulations for the N-terminal 88 amino acids of c-MYC. Comparisons of the simulation data with experimental secondary structure assignments obtained by NMR establish a particular implicit solvation approach as highly congruent. The results provide insights into the structural dynamics of c-MYC1-88, which will be useful for guiding future experimental approaches. The protocols for trajectory analysis described here will be applicable for the analysis of a variety of computational simulations of intrinsically disordered proteins.
Highlights
Disordered proteins (IDPs) exhibit vastly different structural dynamics as compared to folded proteins
The explicitly solvated simulations started with a conventional molecular dynamics simulation that included two successive minimizations: Min1 consisted of a solvent minimization run with the protein fixed, 10,000 maximum cycles and 5000 ncycles of steepest descent; Min2 aimed for a total system minimization with 2500 maximum cycles and 1000 ncycles of steepest descent
molecular dynamics (MD) simulation and convergence analyses were applied to the experimental data available for two human Intrinsically disordered proteins (IDPs) protein models, Histatin 5 and the N-terminal domain of the human oncoprotein c-MYC
Summary
Disordered proteins (IDPs) exhibit vastly different structural dynamics as compared to folded proteins. Instead of folding predictably, according to their amino acid sequence, IDPs exist as a rapidly changing ensemble of conformations. This structural diversity allows them to bind multiple interaction partners, and places them at the center of key cellular pathways [1]. IDPs are enriched in polar and charged residues and depleted in hydrophobic amino acids required for the formation of stable cores. This destabilizes the protein fold and allows IDPs to change rapidly between a wide range of alternate conformations [2].
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