Journal of Chemical Theory and Computation, Journal Year: 2025, Volume and Issue: unknown
Published: April 16, 2025
Collective variable (CV) identification is challenging in complex dynamical systems. To study the translocation of a single-subunit RNA polymerase (RNAP) during human mitochondrial transcription, we employed all-atom molecular dynamics (MD) as vehicle to illustrate CV refinement conformational samplings and dimension reduction analyses. RNAP an essential mechanical step transcription elongation that dictates gene expression. The generally follows from polymerization product release proceeds initial binding or preinsertion incoming nucleotides. DNA-dependent (or POLRMT) plays critical role cellular metabolism can be key off-target design nucleotide analogue antiviral antitumor drugs due its structural similarities with many viral RNAPs RNA-dependent polymerases (RdRps). While POLRMT shares particularly high similarity bacteriophage T7 RNAP, previous experimental studies our current simulations suggest POLRMT's mechanochemical coupling mechanisms may distinct. In work, modeled complexes performed equilibrium MD on pre- post-translocation models, extensive around two potential paths (with without fingers subdomain change). We then compared time-lagged independent component analysis (tICA) neural network implementation variational approach for Markov processes (VAMPnets) dimensional methods selected atomic coordinate sets best represent sampled features simulations. Our results indicate likely coupled NTP enable opening at which would otherwise nonstabilized, translocations proceed futilely incorporation. time scale reaches over hundreds microseconds, predicted by VAMPnets Such seems match last postcatalytic kinetic suggested cycle measurements. simulation combining refinements analyses top thus variation Brownian ratcheting translocation, if motions are binding, captures transient couple sustained opening.
Language: Английский