The Kelvin-Helmholtz Rayleigh-Taylor (KH-RT) breakup model has been extensively utilized in fuel spray simulations. In the KH-RT model, there are five important empirical model parameters, which need to be calibrated carefully for different fuels under various operating conditions. In this work, the global sensitivity analysis of the model constants in the KH-RT breakup model reveals that the model constant for switching the KH and RT mechanisms, C<sub>b</sub>, is a dominant parameter affecting the simulation accuracy with the variation of fuel type. To determine the optimal C<sub>b</sub> for gasoline spray, the computational fluid dynamics (CFD) program of spray simulation is coupled with an evolutionary genetic algorithm to obtain a quantitative relationship between C<sub>b</sub> and ambient density (ρ<sub>amb</sub>). Compared with diesel spray, C<sub>b</sub> for gasoline spray is reduced owing to its lower density, viscosity, and surface tension, making it easier for gasoline spray to form smaller droplets after injection. Therefore, the influence of fuel properties should be considered when optimizing C<sub>b</sub>. By elucidating the correlation between the physical properties of different fuels and their respective optimal C<sub>b</sub> values, this formula is extended to encompass dimethyl ether (DME), biodiesel, and methanol in the present study. The validation results affirm that the enhanced C<sub>b</sub> formula effectively reproduces the evolution of the spray for a variety of fuels, aligning well with experimental measurements.