Abstract Coarse-grained elastic models with a C α -only representation and harmonic interactions have been increasingly used to describe the conformational motions and flexibility of various proteins. In this work, we will unify two complementary elastic models—the elastic network model (ENM) and the Gaussian network model (GNM), in the framework of a generalized anisotropic network model (G-ANM) with a new anisotropy parameter, f anm. The G-ANM is reduced to GNM at f anm = 1, and ENM at f anm = 0. By analyzing a list of protein crystal structure pairs using G-ANM, we have attained optimal descriptions of both the isotropic thermal fluctuations and the crystallographically observed conformational changes with a small f anm ( f anm ≤ 0.1) and a physically realistic cutoff distance, R c ∼ 8 Å. Thus, the G-ANM improves the performance of GNM and ENM while preserving their simplicity. The properly parameterized G-ANM will enable more accurate and realistic modeling of protein conformational motions and flexibility.