Full kinetics of CO entry, internal diffusion, and exit in myoglobin from transition-path theory simulations

Tang Qing Yu, Mauro Lapelosa, Eric Vanden-Eijnden, Cameron F. Abrams

Research output: Contribution to journalArticlepeer-review


We use Markovian milestoning molecular dynamics (MD) simulations on a tessellation of the collective variable space for CO localization in myoglobin to estimate the kinetics of entry, exit, and internal site-hopping. The tessellation is determined by analysis of the free-energy surface in that space using transition-path theory (TPT), which provides criteria for defining optimal milestones, allowing short, independent, cell-constrained MD simulations to provide properly weighted kinetic data. We coarse grain the resulting kinetic model at two levels: first, using crystallographically relevant internal cavities and their predicted interconnections and solvent portals; and second, as a three-state side-path scheme inspired by similar models developed from geminate recombination experiments. We show semiquantitative agreement with experiment on entry and exit rates and in the identification of the so-called "histidine gate" at position 64 through which ≈90% of flux between solvent and the distal pocket passes. We also show with six-dimensional calculations that the minimum free-energy pathway of escape through the histidine gate is a "knock-on" mechanism in which motion of the ligand and the gate are sequential and interdependent. In total, these results suggest that such TPT simulations are indeed a promising approach to overcome the practical time-scale limitations of MD to allow reliable estimation of transition mechanisms and rates among metastable states.

Original languageEnglish (US)
Pages (from-to)3041-3050
Number of pages10
JournalJournal of the American Chemical Society
Issue number8
StatePublished - Mar 4 2015

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry


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