Potential of Mean Force and Umbrella Sampling Simulation for the
Transport of 5-Oxazolidinone in Heterotetrameric Sarcosine Oxidase
Abstract
The structure of heterotetrameric sarcosine oxidase (HSO) contains a
highly complex system composed of a large cavity and tunnels, which are
essential for the reaction and migration of the reactants, products, and
intermediates. Previous molecular dynamics (MD) simulation of HSO has
identified the regions containing the water channels from the density
distribution of water. The simulation is consistent with the selective
transport hypothesis of the migration of the iminium intermediate,
5-oxazolidinone (5-OXA), of the enzyme reaction whereby tunnel T3 is the
exit pathway of 5-OXA. In the present study, the potential of mean force
(PMF) for the transport of 5-OXA through tunnels T1, T2, and T3 was
calculated using umbrella sampling (US) MD simulations and the weighted
histogram analysis method. The maximum errors of the calculated PMF were
estimated by repeating the US simulations using different sets of
initial positions. The PMF profiles for the three tunnels support the
notion that tunnel T3 is the exit pathway of 5-OXA and that 5-OXA tends
to stay at the middle of the tunnel. The PMF profile for the transport
of glycine through tunnel T3 was also calculated to investigate where
5-OXA is converted into glycine, and how glycine is released to the
outside of HSO was explained.