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Fig.?2B shows the restrained Arg at the bilayer center. During the whole simulation process, no water pore was formed spontaneously, and?a water defect on one side of the bilayer was formed. Previous studies have suggested a mechanism of translocating CPPs through a lipid bilayer involving Selleckchem Erlotinib the formation of?a?water pore (18?and?19). However, in simulation A, we did not observe the spontaneous formation of a water pore. We reason that the pore-forming DOF might belong to the?slow-relaxing DOFs and there is a activation energy required for the process. Thus, we use a different OP to direct the system to a translocating path involving a pore. In simulation B, we apply biased potentials on the cylinder OP to force the bilayer to form a water pore. Fig.?3Ashows the PMF of transferring an Arginine from the binding MCF2L position into the bilayer along the cylinder OP. The cylinder OP restraint restricted the distance between pulled Arg and the phosphate atoms contained in the lower leaflets, within the cylinder boundary. Shortening the distance resulted in pulling both the Arg and phosphate atoms within the cylinder boundary inside the bilayer, therefore creating a pore. The kink in the PMF shown in Fig.?3A marks the starting position at which a water pore was formed. A configuration chosen from the umbrella window constrained at the kink position is shown in Fig.?4A(with water) and Fig.?4B (without water). In Fig.?4B, we observe that a lipid could flip deep inside the bilayer to interact Ponatinib mw with the peptide. When a lipid from the lower leaflet flipped, a water defect extended from the lower leaflet began to touch the upper-layer water defect, mimicking the rudiments of a water pore. The discontinuity of the free-energy profile at 1.8?nm in Fig.?3A marks the intersection between the two free-energy surfaces. After a water pore was formed, transferring the Arginine further into the bilayer was no longer the same as transferring through the bilayer hydrophobic core. We observe that the PMF flattened in the region between 1.5?nm and 1.8?nm. To compare with the PMF calculated from simulation A, we projected the data in simulation B onto the position OP. Equation 2 is used to assign an unbiased probability to each datum in simulation B and Eq. 3 is used construct a PMF along the position OP. The projected PMF is plotted as the red line in Fig.?2A. A water pore formed when the restrained Arg was 0.5?nm away from the bilayer center. The projected PMF with position OP?