How Does the Spliceosome Catalyze Intron Lariat Formation? Insights from Quantum Mechanics/Molecular Mechanics Free-Energy Simulations

• DOI: 10.1021/acs.jpcb.9b04377
• Publication Date: 2019-06-19T20:00:36Z
• Authors: Wenting Huang; Yan Huang; Jun Xu; Jie-Lou Liao
• Keywords: Spliceosome; Molecular mechanics; Reaction coordinate

The spliceosome catalyzes nuclear pre-mRNA splicing via formation of an intron lariat and is arguably the most complex macromolecular machine in eukaryotic cells. Intron a conservative feature reaction for both spliceosomal group II introns. Despite importance splicing, atomic-level understanding mechanism remains elusive. In this work, quantum mechanics molecular method with thermodynamic integration used to calculate free-energy profile along pathway. results demonstrate that catalytic Mg2+ ion does not act as Lewis acid activate nucleophile formed dissociative transition state stabilized by electrostatic interactions two ions. Proton transfer occurs from leaving oxygen through phosphate substrate after reached, which important stabilization intron-lariat product efficiency splicing. two-metal-ion proposed study provides novel insight into catalyzed spliceosome.