Conformational flexibility of proteins has been linked to their designated functions. Slow conformational fluctuations occurring at the microsecond to millisecond time scale, in particular, have recently attracted considerable interest in connection to the mechanism of enzyme catalysis. Computational methods are providing valuable insights into the connection between protein structure, flexibility, and function. In this report, we present Studies oil identification and characterization of microsecond flexibility of ubiquitin, based on quasi-harmonic analysis (QHA) and normal-mode analysis (NMA). The results indicate that the slowest 10 QHA modes, Computed from the 0.5 us molecular dynamics ensemble, contribute over 78% of all motions. The identified slow movements show over 75% similarity with the conformational fluctuations observed in nuclear magnetic resonance ensemble and also agree with displacements in the set of X-ray structures. The slowest modes show high flexibility in the beta 1-beta 2, alpha 1-beta 3, and beta 3-beta 4 loop regions, with functional implications in the mechanism of binding other proteins. NMA Of ubiquitin structures was not able to reproduce the long time scale fluctuations, as they were found to strongly depend on the reference structures. Further, conformational fluctuations Coupled to the cis/trans isomerization reaction catalyzed by the enzyme cyclophilin A (CypA), occurring at the microsecond to millisecond time scale, have also been identified and characterized oil the basis of QHA of conformations sampled along the reaction pathway. The results indicate that QHA covers the same conformational landscape as the experimentally observed CypA flexibility. Overall, the identified slow conformational fluctuations ill ubiquitin and CypA indicate that the intrinsic flexibility of these proteins is closely linked to their designated functions.