The rotational diffusion of proteins is an important hydrodynamic property. Compact protein structures were found previously to exhibit hydration layer viscosity, eta(loc), higher than the viscosity of bulk water, eta. This implies an apparent activation energy for rotational diffusion higher than the activation energy of water viscosity, E-eta = 15.4 +/- 0.3 kJ/mol. In this study we examine eta(loc) of internally mobile proteins using N-15 spin relaxation methods. We also examine the activation enthalpy, Delta H-#, and activation entropy, Delta S-#, for rotational diffusion. Of particular relevance are internally mobile ligand-free forms and compact ligand-bound forms of multidomain proteins. Adenylate kinase (AKeco) and Ca2+-calmodulin (Ca2+-CaM) are typical examples. For AKeco (Ca2+- CaM) we find that Delta H-# is 14.5 +/- 0.5 (15.7 +/- 0.4) kJ/mol. For the complex of AKeco with the inhibitor AP(5)A (the complex of Ca2+-CaM with the peptide smMLCKp), we find that Delta H-# is 18.1 +/- 0.7 (18.2 +/- 0.5) kJ/mol. The internally mobile outer surface protein A has Delta H-# = 12.6 +/- 0.8 kJ/mol, and the compact protein Staphylococcal nuclease has Delta H-# = 18.8 +/- 0.6 kJ/mol. For the internally mobile and compact proteins studied, equals 62 +/- 7 J/(mol K) and 44 +/- 5 J/(mol K), respectively. The fact is that eta(loc) > eta (Delta H-# > E-eta) for compact proteins was ascribed previously to electrostatic interactions between surface sites and water rigidifying the hydration layer. We find herein that obliteration of these interactions by domain motion leads to eta(loc) similar to eta, Delta H-# similar to E-eta and large activation entropy for internally mobile protein structures.