Since years 3D-CFD engine simulation was focused in modelling the engine and its components in order to deeply analyse the in-cylinder events that characterize combustion and emission’s formation. The optimization process that followed the modelling part aimed to modify specific parts of the engine assembly as combustion chamber geometry, piston shape, injector position, injection strategy in order to improve combustion behaviour and pollutants’ emission. This process has always been performed keeping fixed the fuel composition since it was not an adjustable parameter. Nowadays with the introduction of new synthetic fuels (e-Fuels) it is possible to manipulate the related chemical composition, thus this innovation requires also new engine simulation methodologies in order to take into account the effect of the fuel parameter on results in terms of combustion behaviour and emission.