| The structures and transportation properties of water molecules in the three transmembrane cyclic peptide nanotubes 8×cyclo (WL)n=3,4,5-PNT/POPE with internal diameters of 6, 8 and 10 ?, respectively, have been investigated by equilibrium and non-equilibrium molecular dynamics (MD) simulations. The studies include the structures of the water chains, orientations of water molecular dipoles, density distributions, osmotic and diffusion features, etc. The main achievements are shown as follows.1. The energy-minimized configurations of the 8×cyclo (WL)n=3,4,5-PNT have been obtained by simulated annealing and followed by MD simulation. The stabilities of the backbones of cyclic peptide nanotubes were studied. Equilibrated configuration of fully hydrated POPE bilayer has been obtained through the MD pre-equilibrium, showing that the effective thickness and area per lipid of the equilibrated POPE bilayer remain constant. Equilibrated configurations of 8×cyclo (WL)n=3,4,5-PNT embedded in the hydrated equilibrated POPE bilayer were obtained from MD equilibrium simulation.2. Water transportation in the 8×cyclo(WL)4-PNT/POPE was performed by 50-ns equilibrium MD. The structure of the water chain and the corresponding formation mechanism inside the nanotube have been discussed in detail. A wavelike pattern of the water chain in the nanotube exists, arraying in the form of 1-2-1-2 file, that is, one H2O molecule in aα-plane zone and two H2O molecules in a mid-plane zone. The wavelength of the distribution profile of water molecules is about 4.8 ?, equal to the distance between two adjacent rings.(1) Cylindrical distribution functions of water molecules at different zones and PMF (potential of mean force) of a water molecule along the nanotube axis suggest that the primary reason for forming the water chain pattern is the nanotube's steric constraints. The radial distribution functions for water molecules inside the nanotube 8×cyclo(WL)4- PNT/POPE give a reasonable explanation for the water chain structure. The probability of a water molecule in a mid-plane zone forming a strong H-bond with the backbone of the peptide nanotube is no more than 10%, indicating that the H-bond interactions between 8×cyclo(WL)4-PNT and water molecules are not major factor for the formation of the water chain stucture. The H-bond network in the nanotube is present, that is, each water in aα-plane zone forms two H-bonds with the two water molecules in the adjacent mid-plane zone, and each water molecule in a mid-plane zones forms one hydrogen bond with the water molecule in the adjacentα-plane zone and one poor H-bond with a carbonyl groups of the nanotube.(2) The dipole orientation distribution of water molecules and the potential energy scan of a water molecule along the PNT axis show that the force acted by the peptide, lipid bilayer and bulk water has a strong orienting effect on water molecular dipoles near the two ends of the nanotube. In the center of the nanotube, these interactions are not strong enough to overcome the molecular thermal motion.3. Equilibrium and non-equilibrium MD simulations have been applied to investigate the transportation proporties of water molecules in the three transmembrane cyclic peptide nanotubes 8×cyclo (WL)n=3,4,5-PNT/POPE. The transportation features of water molecules inside these nanotubes and the characteristic parameters of diffusion (pd) and osmotic permeability (pf) have been obtained.(1) In the 8×cyclo (WL)3-PNT/POPE, water molecules inside the channel array in single-file and most of the water molecules are in the mid-plane zones. In the 8×cyclo (WL)4-PNT/POPE, water molecules form the 1-2-1-2 water-chain pattern. In the 8×cyclo(WL)5-PNT/POPE, the arrangement of water molecules is similar to the structure of bulk water.(2) The movement of water molecules in the 8×cyclo (WL)n = 3,4,5-PNT/POPE is one-dimensional diffusion along the PNT axis, meeting the Fick sports.(3) Characteristic parameter pd of water molecules in the three transmembrane cyclic peptide nanotubes 8×cyclo (WL)n = 3,4,5-PNT/POPE have been obtained firstly by equilibrium MD simulation. Their values are 0.488, 21.17 and 94.08 ?3/ns, respectively. By using equilibrium and non-equilibrium MD simulations, the values of pf were determined firstly, which are 3.97, 66.15 and 496.86 ?3/ns (from equilibrium MD) and 2.30, 71.85 and 473.31 ?3/ns (from non-equilibrium MD). Comparison of the pf/pd values of the three cyclic peptide nanotubes with the data of +1 ( denotes the average number of water molecules inside a channel) shows that the pf/pd value only in the 8×cyclo (WL)3-PNT/POPE is approximately equal to +1, indicating the water molecules move in a concerted fashion with no exchanging and crossing, in accordance with the single-file transportation. With the increase of the diameter of the cyclic peptide nanotube, the water chain in it is no longer in a single-file form and the value of (+1) /(pf/pd) becomes larger.In summary, with the simulations of cyclic peptide nanotubes 8×cyclo (WL)n = 3,4,5-PNT embedded in a fully hydrated POPE bilayer modeling biological water channels, the structures of the water chains in the transmembrane nanotubes and the corresponding formation mechanism have been analyszed. The diffusion and osmotic properties of such nanotubes were firstly probed. The results will contribute to reveal some basical features of water channels with nano-scales at the atomic level.
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