A model was proposed to simulate a distillation column where the feed contains multi-PONA hydrocarbons. The importance of the exact thermodynamic method and parameters fitting experimental VLE data well on simulation results were demonstrated. Based on the similarity of the boiling points of the same-carbon-number PONA species, the concept of light and heavy key groups was proposed and introduced into the objective function that is minimized to determine the overall column efficiency. Different from single light key and heavy key generally used, the key groups take into account of the interactions of various molecular structures. Therefore, their effects on vapor-liquid equilibrium could be totally or partially added in the objective function, thus increasing the accuracy of determined column efficiency especially for a multi-PONA hydrocarbon system.