This work employs in situ measurement data and constructive simulations to examine the underlying physical mechanisms that drive spacecraft plume interactions with the space environment in low-Earth orbit. The study centers on observations of the enhanced flux of plasma generated during a maneuver of Space Shuttle Endeavour as part of the Sensor Test for Orion Relative Navigation Risk Mitigation experiment in May 2011. The Canary electrostatic analyzer (ESA) instrument mounted on the portside truss of the International Space Station indicated an elevated ion current during the shuttle maneuver. The apparent source of enhanced ion current is a result of interaction of the spacecraft thruster plume with the rarefied ambient ionosphere, which generates regions of relatively high density plasma through charge exchange between the neutral plume and ambient ions. To reconstruct this event, unsteady simulation data were generated using a combined direct simulation Monte Carlo/particle-in-cell methodology, which employed detailed charge exchange cross-section data and a magnetic field model. The simulation provides local plasma characteristics at the ESA sensor location, and a sensor model is subsequently used to transform the local properties into a prediction of measured ion current. The predicted and observed total currents are presented as a function of time over a 30 s period of pulsed thruster firings. A strong correlation is observed in the temporal characteristics of the simulated and measured total current, and good agreement is also achieved in the total current predicted by the model. These results support conclusions that (1) the enhanced flux of plasma observed by the ESA instrument is associated with Space Shuttle thruster firings and (2) the simulation model captures the essential features of the plume interactions based on the observation data.