Mechanistic Insights into Glycosylation-Driven Structural Rearrangements in Human Aquaporin 1

Abstract

The asparagine-linked glycosylation site of the extended extracellular loop connecting transmembrane helices 1 and 2 has been identified in human aquaporin 1 (AQP1), though its functional significance remains unclear. Here, we investigate AQP1 glycosylated at Asn42 and Asn205, using molecular dynamics simulations. In glycosylated AQP1, fluctuation of the protein backbone groups surrounding the linker Asn42 in the extended extracellular loop 1-2 is significantly suppressed compared to non-glycosylated AQP1. Remarkably, glycosylation induces disorder in water molecules along the channel pore. The heavily hydrated glycan at Asn42 suppresses loop 1-2 flexibility and stretches the loop, facilitating the formation of a salt bridge between Lys36 (helix 1) and Asp185 (loop 5-E, connecting helices 5 and E). This interaction triggers rearrangements in transmembrane helices 1 and 5, widening the channel pore. The observed glycosylation-induced structural modulation may represent a common regulatory mechanism among AQP family proteins.