Herein we investigate the potential of novel methods of molecular dynamics analysis to provide information on the key factors that underlie the preferential localization and the effects of mutations modulating protein activities. Epidermal growth factor receptor (EGFR) kinases are selected as a test case. The combined analysis of protein energetics and internal dynamics indicates a clear polarization in the native protein, whereby a highly stable and ordered scaffold in one domain, namely the C-lobe, is combined to a flexible and loosely stabilized domain, the N-lobe. The subdivision in two portions with different properties directs the presence of point mutations mainly to the N-lobe. This allows modulating protein flexibility so that the protein can more efficiently sample the conformations necessary for substrate recognition, while leaving the stability of the protein unperturbed. In this context, comparative simulations of EGFR in the wild type sequence and in the presence of the activating oncogenic mutation G719S reveal flexibility changes in several key regions, involving in particular the part of the kinase devoted to the regulation of substrate recognition (regulatory core) and an increase in the number of stabilizing interactions in the N-lobe for the activated mutant. Our approaches represent a promising and simple strategy toward rationalizing the effects of mutations in modulating enzymatic activities.