However, the use of Boresch restraints in combination with RMSD-based restraints on the conformation of the ligand may prove similarly effective. This scheme is in some ways similar to the DBC scheme, in that a complex restraint (set of restraints) involving many degrees of freedom is released to a single harmonic restraint to allow the calculation of ∆G o Release . While the DBC restraint is attractively simple -it consists of a single flat-bottomed restraint on the RMSD of a subset of ligand coordinates in the frame of reference of the binding site -multiple distance restraints schemes offer finer control over the strength of restraints applied to different subsections of the system. This may be beneficial, for example in the case of a large and flexible ligand where only part of the ligand interacts strongly with the receptor. If the coordinates of all ligand heavy atoms were included in the DBC restraint, then the DBC coordinate would show very wide fluctuations during simulations of the bound state. Fitting the DBC restraint to encompass the 95th percentile of sampled DBC coordinates would result in a very weak restraint on all sections of the ligand, which may result in sampling issues. Flat-bottomed multiple distance restraints could be fit in a similar way, such that the flat-bottomed regions encompassed almost all distances measured during a simulation of the fully-interacting complex. In contrast to the DBC restraints fit to all ligand heavy atoms, the multiple distance restraints fit to all heavy atoms would closely restrict the portion of the ligand which interacts strongly with the receptor, while allowing large fluctuations in the flexible portion which does not. While multiple distance restraints require many more parameters than the DBC restraint, they can be automatically selected from a simulation of the fully interacting complex using algorithms described in this work. Furthermore, if the user opted not to run such a simulation for restraint selection, distance restraints could be intuitively selected to match receptor-ligand interactions, and reasonable default parameters could be chosen. It may be challenging to select a reasonable flat-bottomed region for a DBC restraint without a trajectory.