Enhanced sampling by multiple molecular dynamics trajectories: carbonmonoxy myoglobin 10 μs A 0 → A 1–3 transition from ten 400 picosecond simulations

Abstract

The utility of multiple trajectories to extend the time scale of molecular dynamics simulations is reported for the spectroscopic A-states of carbonmonoxy myoglobin (MbCO). Experimentally, the A 0→A 1–3 transition has been observed to be 10 μs at 300 K, which is beyond the time scale of standard molecular dynamics simulations. To simulate this transition, 10 short (400 ps) and two longer time (1.2 ns) molecular dynamics trajectories, starting from five different crystallographic and solution phase structures with random initial velocities centered in a 37 Å radius sphere of water, have been used to sample the native-fold of MbCO. Analysis of the ensemble of structures gathered over the cumulative 5.6 ns reveals two biomolecular motions involving the side chains of His64 and Arg45 to explain the spectroscopic states of MbCO. The 10 μs A 0→A 1–3 transition involves the motion of His64, where distance between His64 and CO is found to vary up to 8.8±1.0 Å during the transition of His64 from the ligand (A 1–3) to bulk solvent (A 0). The His64 motion occurs within a single trajectory only once, however the multiple trajectories populate the spectroscopic A-states fully. Consequently, multiple independent molecular dynamics simulations have been found to extend biomolecular motion from 5 ns of total simulation to experimental phenomena on the microsecond time scale.