Mechanistic insights into the cooperative permeation of glycerol and water by human aquaporin-10

Human aquaporins are integral membrane proteins that facilitate the transport of small molecules across the membrane. Among the 13 members of this family, the pH-regulated human aquaporin-10 (hAQP10) plays a critical role in glycerol metabolism and lipid homeostasis. A molecular-level understanding of water and glycerol transport through hAQP10 nanopores is essential to enable rational therapeutic interventions. We present an atom molecular dynamics (MD) simulation study characterizing the nanostructure, thermodynamic stability, and glycerol permeability of tetrameric hAQP10 channels embedded in lipid bilayer membranes. Using equilibrium and forward sampling MD simulations, we study the cooperative diffusion of water and glycerol through the channel. The free energy landscape (ΔG) derived from extensive sampling simulations of homologous exchange reveals multiple binding sites and energy barriers of a few kB_forT along the channel axis. By integrating the profile (ΔG) with the heterogeneous solute diffusion model, we estimate the permeability of single-channel glycerol diffusion through hAQP10 to be 4 × 10^-17 poison³/s at a concentration of 100 mM. The residence times of glycerol in the channel during unbiased simulations range from nanoseconds to microseconds. The transport kinetics, characterized using a theoretical model derived from simulated trajectories of coarse atoms, indicates an average first-pass time of several microseconds. Directed molecular dynamics simulations comparing the permeation energetics of water and glycerol reveal similar barriers in the open conformation. Together, these results provide a comprehensive quantitative picture of glycerol and water permeation through hAQP10, with potential implications in understanding the physiological role of hAQP10 in human health.