Metal-organic frameworks (MOFs) have gained much attention as next-generation porous media for various applications, especially gas separation/storage, and catalysis. New MOFs are regularly reported; however, to develop better materials in a timely manner for specific applications, the interactions between guest molecules and the internal surface of the framework must first be understood. A combined experimental and theoretical approach is presented, which proves essential for the elucidation of small-molecule interactions in a model MOF system known as M-2(dobdc) (dobdc(4-) = 2,5-dioxido-1,4-benzenedicarboxylate; M = Mg, Mn, Fe, Co, Ni, Cu, or Zn), a material whose adsorption properties can be readily tuned via chemical substitution. It is additionally shown that the study of extensive families like this one can provide a platform to test the efficacy and accuracy of developing computational methodologies in slightly varying chemical environments, a task that is necessary for their evolution into viable, robust tools for screening large numbers of materials.