title: Oxygen Pathways and Allostery in Monomeric Sarcosine Oxidase via Single-Sweep Free-Energy Reconstruction.
abstract: Monomeric sarcosine oxidase (MSOX) is a flavoprotein D-amino acid oxidase with reported sarcosine and oxygen activation sites on thereandsifaces of the flavin ring, respectively. O2transport routes to the catalytic interior are not well understood and are difficult to ascertain solely from MSOX crystal structures. A composite free-energy method known as single-sweep is used to map and thermodynamically characterize oxygen sites and routes leading to the catalytically active Lys265 from the protein surface. The result is a network of pathways and free energies within MSOX illustrating that oxygen can access two free-energy minima on thereface of the reduced flavin from four separate solvent portals. No such minimum is observed on thesiface. The pathways are geometrically similar for three major states of the enzyme: (1) apo with a closed flavin cleft, (2) apo with an open flavin cleft, and (3) inhibitor-bound with a closed flavin cleft. Interestingly, free energies along these transport pathways display significantly deeper minima when the substrate-mimicking inhibitor 2-furoic acid is bound at the sarcosine site, even at locations far from this site. This suggests a substrate-dependent allosteric modulation of the kinetics of O2transport from the solvent to the active site.
authors: Dept. Chemical and Biological Engineering, Drexel University , Philadelphia, Pennsylvania 19104, United States.
authors: Anthony
authors: A
authors: Bucci
authors: Dept. Chemical and Biological Engineering, Drexel University , Philadelphia, Pennsylvania 19104, United States.
authors: Cameron F
authors: CF
authors: Abrams