Although the errors in the total energies compared to a supermolecular calculation remain rather large in all cases, we expect a higher accuracy for relative energies (see Section 3.3 below). However, the MFCC-MBE(2) method comes with a substantially increased computational effort and a quadratic scaling of the number of single-point calculations with the system size. As shown in Table , the total number of single-point calculations which have to be performed is 11,104. Here, the fragments and caps are the single monomers as used in the standard MFCC scheme. The fragment-fragment, fragment-cap, and cap-cap interactions each require calculations for dimers. This leads to a high computational cost and becomes infeasible already for a relatively small protein such as ubiquitin.