Flexible metal–organic frameworks (MOFs) undergo structural transformations in response to physical and chemical stimuli. This is hard to control because of feedback between guest uptake and host structure change. We report a family of flexible MOFs based on derivatized amino acid linkers. Their porosity consists of a one-dimensional channel connected to three peripheral pockets. This network structure amplifies small local changes in linker conformation, which are strongly coupled to the guest packing in and the shape of the peripheral pockets, to afford large changes in the global pore geometry that can, for example, segment the pore into four isolated components. The synergy among pore volume, guest packing, and linker conformation that characterizes this family of structures can be determined by the amino acid side chain, because it is repositioned by linker torsion. The resulting control optimizes noncovalent interactions to differentiate the uptake and structure response of host–guest pairs with similar chemistries.