The overall analysis indicates that LEAPs are not a protein subset of hydrophilins family. Hydrophilins are rather related to LEAP class 2 and to HSP12. It also suggests and/or confirms that LEAP class 2, hydrophilins and WHy domain interact with water or other polar/charged small molecules, and thus could share a common physiological role in dehydration tolerance. It has been shown that HSP12 from yeast is a hydrophilin. HSP12 is also an IDP that modulates TWS119 inhibitor membrane function. We have included HSP12 in our analysis as an additional dataset in order to compare it with LEAPs and hydrophilin. WHy domain is characterized by the highest level of mean molar fraction of buried residues and the lowest level of mean molar fraction of accessible residues. This domain is likely compact with small cavities, if any, that can accommodate only small molecules. One of the best-documented LEAP’s functions is their interaction with water and some polar cellular compounds. Moreover, all LEAP classes are IDP. This structural characteristic allows them to sequester water and sugars in a tightly hydrogenbonded network. Thus, one of their noticeable physical properties is their ability to establish hydrogen bonds. The physico-chemical complexity of protein surfaces alters the structure of the surrounding layer of hydrating water molecules: hydration waters have slower correlation times than water in bulk. Hydrogen bonds are established by area composed mainly by polar or polarizable amino acids such as Asn, Gln and Gly. The resulting area interacts more easily with polar molecules, especially water. WHy domain is composed of alternating hydrophobic and hydrophilic residues with an invariant NPN motif near its N-terminal extremity. A similar signature linked to a crucial role in water transport is found in aquaporin. It is possible that hydrophobic pockets create a barrier orienting the water molecule’s dipole moment near the NPN motif. Interactions between amino acids side chains and waters contribute to the stabilization of the native, thus functional, protein conformation. The interactions between water molecules and a small hydrophobic pentapeptide, have been studied at controlled levels of hydration, by adding successively, up to 25 water molecules per peptide . The first added water molecules form naturally bonds with the hydrophilic part of the pentapeptide while the next added ones are confined to the surface of alanine without bond formation. Plants exhibit a surveillance system based on disease resistance gene to recognize avirulence factors displayed by pathogens. Among defense responses activated after pathogen recognition, one is called hypersensitive response. Some proteins are coded NHL genes. WHy domain links NHL proteins to the plant family LEA-14. A link exists also between LEAPs class 6 . Thus, it is likely that WHy domain play an important physiological role against pathogens-induced stress. A protective role of hydrophilins against enzyme inactivation due to water limitation has been demonstrated. They act as membrane and protein stabilizers during water stress, either by direct interaction or by acting as a molecular shield.