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

Donghui Wei, Mingsheng Tang, Chang Guo Zhan

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


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-Oγ directly by Thr1-Nz to form a zwitterionic intermediate. The next step is a nucleophilic attack on the olefin carbon of SylA by the negatively charged Thr1-Oγ atom. The last step is a proton transfer from Thr1-Nz to another olefin carbon of SylA to complete the inhibition reaction process. The calculated free energy profile demonstrates that the second step should be the rate-determining step and has the highest free energy barrier of 24.6 kcal mol-1, which is reasonably close to the activation free energy (∼22.4-23.0 kcal mol-1) derived from the available experimental kinetic data. In addition, our computational results indicate that no water molecule can assist the rate-determining step, since the second step is not involved in a proton transfer process. The obtained mechanistic insights should be valuable for understanding the inhibition process of proteasome by SylA and structurally related inhibitors at a molecular level, and thus provide a solid mechanistic base and valuable clues for future rational design of novel, more potent inhibitors of proteasome.

Original languageEnglish
Pages (from-to)6857-6865
Number of pages9
JournalOrganic and Biomolecular Chemistry
Issue number24
StatePublished - Jun 28 2015

Bibliographical note

Publisher Copyright:
© The Royal Society of Chemistry.

ASJC Scopus subject areas

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry


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