We consider the problem of discriminating macromolecular structures in an electron microscope, through a specific beam shaping technique. Our approach is based on maximizing the which-molecule information extracted from the state of each electron. To this aim, the optimal observables are derived within the framework of quantum state discrimination, which allows one to fully account from the quantum character of the probe. We simulate the implementation of such optimal observable on a generalized orbital angular momentum (OAM) sorter and benchmark its performance against the best known real space approach.