The definition of the MC region is modified from the prior version of our code to a method that is compatible with all types of simulation boxes (e.g., rectangular prism, truncated octahedron). Here, the MC region in which waters are moved with MC steps is a rectangular prism with user-defined dimensions and centered at the center of coordinates of a user-defined set of atoms selected with the AMBER masking function. This selection is defined with the input keyword mcwatmask, and the keyword mcligshift is used to define the length of the grid along each axis, in Å. For example, a value of 10 means that the grid will extend ±10 Å from the center along each axis. Thus, one may enhance water exchange in a buried binding pocket by centering the MC region on a residue bordering the pocket and making the region large enough that it extends into the water outside the protein. If the grid is not defined, the grid dimensions will be the entire simulation box.