Fundamental reaction pathway and free energy profile of proteasome inhibition by syringolin A (SylA).

ABSTRACT: In this study, molecular dynamics (MD) simulations and first-principles quantum mechanical/molecular mechanical free energy (QM/MM-FE) calculations have been performed to uncover the fundamental reaction pathway of proteasome with a representative inhibitor syringolin A (SylA). The calculated results reveal that the reaction process consists of three steps. The first step is a proton transfer process, activating Thr1-O(γ) directly by Thr1-N(z) to form a zwitterionic intermediate. The next step is a nucleophilic attack on the olefin carbon of SylA by the negatively charged Thr1-O(γ) atom. The last step is a proton transfer from Thr1-N(z) to another olefin carbon of SylA to complete the inhibition reaction process. The calculated free energy profile demonstrates that the second step should b

SUBMITTER: Wei D 

PROVIDER: S-EPMC4472459 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature