title: Full kinetics of CO entry, internal diffusion, and exit in myoglobin from transition-path theory simulations.
abstract: 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.
authors: Courant Institute of Mathematical Sciences, New York University , New York, New York 10012, United States.
authors: Tang-Qing
authors: TQ
authors: Yu
authors: Mauro
authors: M
authors: Lapelosa
authors: Eric
authors: E
authors: Vanden-Eijnden
authors: Cameron F
authors: CF
authors: Abrams
mesh_terms: D001665:Binding Sites; D002248:Carbon Monoxide / Q000378:metabolism*; D004058:Diffusion; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D009211:Myoglobin / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation
chemical_list: D008024:Ligands; D009211:Myoglobin; D002248:Carbon Monoxide