Mechanistic insights into cooperative permeation of glycerol and water through human aquaporin-10.

Abstract

Human aquaporins are integral membrane proteins that facilitate transmembrane transport of small molecules. Among the 13 members of this family, 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 for enabling rational therapeutic interventions. We present an all-atom molecular dynamics (MD) simulation study characterizing the nanoscale structure, thermodynamic stability, and glycerol permeability of tetrameric hAQP10 channels embedded in lipid bilayer membranes. Using equilibrium and advanced sampling MD simulations, we investigate the cooperative diffusion of water and glycerol through the channel. Free energy (ΔG) landscape derived from replica-exchange umbrella sampling simulations reveals multiple binding sites and energy barriers of a few kBT along the channel axis. Integrating the (ΔG) profile with the inhomogeneous solubility-diffusion model, we estimate a single channel diffusive permeability of glycerol through hAQP10 to be 4 × 10-17 cm3/s at a concentration of 100 mM. Glycerol residence times in the channel during unbiased simulations range from nanoseconds to microseconds. Transport kinetics, characterized using a theoretical model derived by coarse-graining all-atom simulation trajectories, indicate a mean first-passage time of several microseconds. Steered molecular dynamics simulations comparing water and glycerol permeation energetics reveal similar barriers in the open conformation. Together, these findings provide a comprehensive quantitative picture of glycerol and water permeation through hAQP10, with potential implications in understanding physiological role of hAQP10 in human health.