Abstract: Disclosed are computational modeling methods employing RMS fluctuation values associated with energy functions to compute binding properties of a subject biomolecule and an identified target. An energy function (or force field) that relates the molecular structure of a biomolecule to an energy value, modified with terms calculated from sets of RMS fluctuation values of the biomolecule, the target and the complex, are used to identify a potential mutation or modification suitable for imparting a selected property to a biomolecule of interest. Uses of the method in the manufacture of non-native proteins having a selected modified property are also provided. Therapeutic agents (proteins, antibodies, TCRs) enzymes, etc., prepared according to the present methods are also provided. Non-native biomolecules having improved properties, for example, weaker or enhanced binding affinity in a modified TCR, are described. Enzymes, industrial reagents, and the like, created using the disclosed methods are also presented.