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.
Kunal Rai, Himanshu Joshi· Proceedings of the National...· 0 citations
Computational modeling tools have enabled detailed exploration of the structural dynamics of nucleic acids at the nanoscale. Despite these developments, a unified platform for creating multiscale models of topological DNA structures, which are of fundamental importance across rapidly converging biological disciplines, is lacking. Here we present a GUI-enabled topological DNA design tool, SketchDNA (SDNA), that facilitates a user-friendly interface to create all-atom (AA) and coarse-grained (CG) models of DNA structures with tunable topological parameters. Building on the modular and open-source framework of SDNA, the software can be readily integrated with both emerging and existing DNA design platforms, such as oxDNA, MrDNA, etc. We demonstrate the utility of SDNA computational framework by simulating the conformational dynamics of three representative topological DNA structures, minicircles, catenanes, and Borromean rings. Analyzing AA and CG molecular dynamics (MD) simulations of these topological DNA systems using the AMBER and Martini DNA force fields, respectively, we characterize their equilibrium structural dynamics, fluctuations, and topological properties. While the AA simulations allow us to characterize the topology-dependent structural rearrangements at the nucleotide level, long-timescale CG simulations reveal supercoiling-induced conformational transitions. The multiscale SDNA toolkit broadens the applications of MD simulations by enabling in-situ characterization of the biophysical properties of topological DNA nanostructures. The GUI version of SDNA is available at https://sdna.biotech.iith.ac.in without registration, while the source code is accessible at GitHub
