The scope of the work presented in this paper was to apply the latest open source CFD achievements to design a state of the art, direct-injection (DI), heavy-duty, natural gas-fueled engine. Within this context, an initial steady-state analysis of the in-cylinder flow was performed by simulating three different intake ducts geometries, each one with seven different valve lift values, chosen according to an estabilished methodology proposed by AVL. The discharge coefficient (Cd) and the Tumble Ratio (TR) were calculated in each case, and an optimal intake ports geometry configuration was assessed in terms of a compromise between the desired intensity of tumble in the chamber and the satisfaction of an adequate value of Cd. Subsequently, full-cycle, cold-flow simulations were performed for three different engine operating points, in order to evaluate the in-cylinder development of TR and turbulent kinetic energy (TKE) under transient conditions. The latest achievements in open source mesh generation and motions were applied, along with time-varying and case-fitted inizialization values for the fields of intake pressure and temperature. Finally, direct-injection of natural gas in the cylinder was incorporated in full-cycle simulations, to evaluate the effects of injection on charge motions and charge homogeneity at the estimated spark timing. Three specific engine operating points were simulated and different combinations of turbochargers and valve lift laws were tested. Results consistency was verified by means of validations with data from 1D simulations and literature.