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We applied a new large two membrane model of human urea transporter B (UT-B) with urea concentration gradient between intracellular and extracellular solution to explore the structure and dynamics of urea permeation. The first solved human UT-B X-ray crystal structure (PDB 6QD5) was studied using atomistic force field based large scale molecular dynamics (MD) simulations. The urea binding sites in UT-B were identified by the combination of first principles molecular dynamics docking and hybrid steered molecular dynamics (hSMD). In the simulations, urea molecules bound to the two binding sites although urea molecules did not go through the channels. The potential of mean force (PMF) of urea along the channel was calculated by hSMD to investigate the selectivity of the urea permeation across the channel pore. The simulations provide an opportunity to explore the binding sites spontaneously to help understand the urea permeation gating and transportation mechanism. A clearer analysis of the selectivity filter is shown in more detail. We also furthered the research about small organic molecules in the specific environment, such as channels in this work. [ABSTRACT FROM AUTHOR]

In order to elucidate how phosphatidylserine (PS6) interacts with AQP5 in a cell membrane, we developed a hybrid steered molecular dynamics (hSMD) method that involved: (1) Simultaneously steering two centers of mass of two selected segments of the ligand, and (2) equilibrating the ligand-protein complex with and without biasing the system. Validating hSMD, we first studied vascular endothelial growth factor receptor 1 (VEGFR1) in complex with N-(4-Chlorophenyl)-2-((pyridin-4-ylmethyl)amino)benzamide (8ST), for which the binding energy is known fromin vitroexperiments. In this study, our computed binding energy well agreed with the experimental value. Knowing the accuracy of this hSMD method, we applied it to the AQP5-lipid-bilayer system to answer an outstanding question relevant to AQP5’s physiological function: Will the PS6, a lipid having a single long hydrocarbon tail that was found in the central pore of the AQP5 tetramer crystal, actually bind to and inhibit AQP5’s central pore under near-physiological conditions, namely, when AQP5 tetramer is embedded in a lipid bilayer? We found,in silico, using the CHARMM 36 force field, that binding PS6 to AQP5 was a factor of 3 million weaker than “binding” it in the lipid bilayer. This suggests that AQP5’s central pore will not be inhibited by PS6 or a similar lipid in a physiological environment. [ABSTRACT FROM PUBLISHER]