What should the Z‐score of native protein structures be?

The Z‐score of a protein is defined as the energy separation between the native fold and the average of an ensemble of misfolds in the units of the standard deviation of the ensemble. The Z‐score is often used as a way of testing the knowledge‐based potentials for their ability to recognize the native fold from other alternatives. However, it is not known what range of values the Z‐scores should have if one had a correct potential. Here, we offer an estimate of Z‐scores extracted from calorimetric measurements of proteins. The energies obtained from these experimental data are compared with those from computer simulations of a lattice model protein. It is suggested that the Z‐scores calculated from different knowledge‐based potentials are generally too small in comparison with the experimental values.