The computational study of ligand binding to a target protein provides mechanistic insight into the molecular determinants of this process and can improve the success rate of in silico drug design. All-atom molecular dynamics (MD) simulations can be used to evaluate the binding free energy, typically by thermodynamic integration, and to probe binding mechanisms, including the description of protein conformational dynamics. The advantages of MD come at a high computational cost, which limits its use. Such cost could be reduced by using coarse-grained models, but their use is generally associated with an undesirable loss of resolution and accuracy. To address the trade-off between speed and accuracy of MD simulations, we describe the use of the recently introduced multi-eGO atomic model for the estimation of binding free energies. We illustrate this approach in the case of the binding of benzene to lysozyme by both thermodynamic integration and metadynamics, showing multiple binding/unbinding pathways of benzene. We then provide equally accurate results for the binding free energy of dasatinib and PP1 to Src kinase by thermodynamic integration. Finally, we show how we can describe the binding of the small molecule 10074-G5 to Aβ42 by single molecule simulations and by explicit titration of the ligand as a function of concentration. These results demonstrate that multi-eGO has the potential to significantly reduce the cost of accurate binding free energy calculations and can be used to develop and benchmark in silico ligand binding techniques.