Molecular dynamics study of water transport through AQP5-R188C mutant causing palmoplantar keratoderma (PPK) using the gating mechanism concept.

It is widely known that any disruption to the water regulation in aquaporins (AQPs) leads to numerous important diseases. However, studies of dynamics and energetics of disease-causing mutations in the aquaporins on the molecular level are still limited. In the present work, the effects of a skin disease-causing mutant, R188C, on the structure of AQP5 and water transport mechanism within this mutated aquaporin are investigated using the concept of gating mechanism. Our results have revealed that the R188C mutation causes a remarkable increase in the pore radius inside the selectivity filter (SF) region facilitating the passage of water molecules. This observation is supported by plotting the free energy profiles of water molecules transport and calculating permeability values through AQP5-R188C, such that the energy barrier in the SF region of the pores was substantially reduced by this mutation, and therefore, the translocation of water molecules was improved. The total averaged osmotic permeability for R188C has been computed as about 11-fold of the wild-type permeability. However, a comparison between the osmotic permeability values related to the open conformation of CE revealed that this coefficient for AQP5-R188C is about 6.5 times larger than that of wt-AQP5, which can be a more accurate value according to the gating mechanism associated with the constriction region of the aquaporin.
(Copyright © 2021. Published by Elsevier B.V.)