A system controls a multi-zone vapor compression system (MZ-VCS). The system includes a controller to control a vapor compression cycle of the MZ-VCS using a set of control inputs determined by optimizing a cost function including a set of control parameters. The optimizing is subject to constraints, and wherein the cost function is optimized over a prediction horizon. The system also includes a memory to store an optimization function parameterized by a configuration of the MZ-VCS defining active or inactive modes of each heat exchanger, the optimization function modifies, according to a current configuration, values of the control parameters of the cost function determined for a full configuration that includes all heat exchangers in the active mode. The system also includes a processor to determine the current configuration of the MZ-VCS and to update the cost function by submitting the current configuration to the optimization function.