Abstract
A combination of molecular dynamics (MD) simulations and computational analyses uncovers structural features that may influence substrate passage and exposure to the active sites within the proteolytic chamber of the 20S proteasome core particle (CP). MD simulations of the CP reveal relaxation dynamics in which the CP slowly contracts over the 54 ns sampling period. MD simulations of the SyringolinA (SylA) inhibitor within the proteolytic ring chamber of the CP indicate that favorable van der Waals and electrostatic interactions account for the predominant association of the inhibitor with the walls of the proteolytic chamber. The time scale required for the inhibitor to travel from the center of the proteolytic chamber to the chamber wall is on the order of 4 ns, accompanied by an average energetic stabilization of approximately −20 kcal/mol.
Highlights
The 26S proteasome complex, found in eukaryotes as well as prokaryotes, is responsible for a range of biological processes, including protein quality control, cell differentiation, antigen processing, signal transduction, cell cycle control, and apoptosis [1]
molecular dynamics (MD) simulations of the SyringolinA (SylA) inhibitor within the proteolytic B1 ring chamber of the core particle (CP) indicate that favorable van der Waals and electrostatic interactions account for the predominant association of the inhibitor with the walls of the proteolytic chamber
We observe smaller root-mean-square deviations (RMSDs) values (∼2–2.5 Å) for the individual CP rings, as compared to the entire CP structure, and for most of the individual ring subunits (α subunits are shown in Figure 4B as an example) RMSD values around 1.5 Å
Summary
The 26S proteasome complex, found in eukaryotes as well as prokaryotes, is responsible for a range of biological processes, including protein quality control, cell differentiation, antigen processing, signal transduction, cell cycle control, and apoptosis [1]. About 150 Å in height and 110 Å in diameter, the 670-kilodalton 20S CP, or multicatalytic protease complex, consists of four heptameric rings, each containing seven subunits, that are stacked on top of each other to form a hollow cylinder [3]. Three of the seven β subunits contain N-terminal proteolytic active centers, β1, β2, and β5 (depicted schematically for the B1 ring in Figure 1B,C), with caspase-like, trypsin-like, and chymotrypsin-like proteolytic activities, respectively [5]
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