Abstract
Unraveling the Molecular Mechanism of Pre-mRNA Splicing From Multi-Scale Simulations.
Highlights
The removal of non-coding introns within a precursor messenger RNA transcript is a key step of gene expression and regulation, occurring via two transesterification reactions mediated by at least two Mg2+ ions (Kastner et al, 2019)
By using classical and QM(Car–Parrinello)/MM molecular dynamics (MD), with the QM part described at Density Functional Theory (DFT)-BLYP level of theory, and the MM part treated with the AMBER- ff12SB force field (FF) (Pérez et al, 2007; Zgarbová et al, 2011; Maier et al, 2015), in combination with thermodynamic integration to enable the reaction event within the limited time-scale of the QM/MM MD simulations, this study unveiled a novel dissociative two-Mg2+-ion mechanism in which the bulk water acts as general base (Casalino et al, 2016)
The subtle molecular foundations ensuring the reliable identification of authentic consensus splice sites, while simultaneously providing some flexibility in the selection of non-consensus ones remain unclear
Summary
The removal of non-coding introns within a precursor messenger RNA (pre-mRNA) transcript is a key step of gene expression and regulation, occurring via two transesterification reactions mediated by at least two Mg2+ ions (Kastner et al, 2019). Recent developments in single-particle cryo-EM have led to elucidate a plethora of near-atomic resolution structures of SPL complexes from human and yeast strains, allowing decades of biochemical, structural and functional studies to be interpreted.
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