© Springer Science+Business Media, LLC, part of Springer Nature 2019. The ability to obtain binding free energies from molecular simulation techniques provides a valuable support to the interpretation and design of experiments. Among all methods available, the most widely used equilibrium free energy methods range from highly accurate and computationally expensive perturbation theory-based methods, such as free energy perturbation (FEP), or thermodynamic integration (TI), through end-point methods, such as molecular mechanics with generalized Born and surface area solvation (MM/GBSA) or MM/PBSA, when the Poisson–Boltzmann method is used instead of GB, and linear interaction energy (LIE) methods, to scoring functions, which are relatively simple empirical functions widely used as part of molecular docking protocols. Because the use of FEP and TI approaches is restricted to cases where the perturbation leading from an initial to final state is negligible or minimal, their application to cases where large conformational changes are involved between bound and unbound states is rather complex, if not prohibitive in terms of convergence. Here we describe a protocol that involves the use of extensive conformational sampling through molecular dynamics (MD) in combination with end-point methods (MM/GB(PB)SA) with an additional quasi-harmonic entropy component, for the calculation of the relative binding free energies of highly flexible, or intrinsically disordered, peptides to a structured receptor.