The binding affinity of nitrogen-containing bisphosphonates (NBPs) to bone mineral surface is important to its uptake, release, and diffusion within bone. However, how molecular structures of NBPs influence the binding affinity has not reached conclusions through experimental measurements. We examined the binding free energies of zoledronate (ZOL), risedronate (RIS), pamidronate (PAM), alendronate (ALN), and ibandronate (IBN) to neat and protonated hydroxyapatite surfaces through molecular dynamics and umbrella sampling. The computed binding free energy rank was ALN > PAM > ZOL > IBN > RIS which was not only qualitatively but also quantitatively consistent with NMR and isothermal titration calorimetry studies.