It was found that the variety of function-related conformational changes (“movements”) in proteins is beyond the earlier simple classifications. Here we offer biochemists a more comprehensive, transparent and easy to use approach allowing a detailed and accurate interpretation of such conformational changes. It makes possible a more multifaceted characterization of protein flexibility by identifying rigidly and non-rigidly repositioned fragments, stable and non-stable fragments, domain and non-domain repositioning. “Coordinate uncertainty thresholds” derived from computed differences between independently determined coordinates of the same molecules are used as the criteria for conformational identity. ‘Identical’ rigid substructures are localized in the distance difference matrices (DDMs). A sequence of simple transformations determines whether a structural change occurs by rigid body “movements” of fragments or largely through non-rigid-body deformations. We estimate the stability of protein fragments and compare stable and rigidly moving fragments. The motions computed with the coarse-grained elastic networks are also compared to their DDM analogs. We study and suggest a classification for 17 structural pairs, differing in their functional states. For 5 of the 17 proteins conformational change cannot be accomplished by rigid-body transformations, and require significant non-rigid body deformations. Stable fragments rarely coincide with rigidly moving fragments, and often disagree with the CATH identifications of domains. Almost all monomeric apo-chains, containing stable fragments/domains, indicate instability of the entire molecule, suggesting the importance of fragments and domains motions prior to stabilization by substrate binding or crystallization. Notably kinases exhibit the greatest extent of non-rigidity among the proteins investigated.