It was recently demonstrated that significant local deformations of biological membranes take place due to the fields of charged peptides and ions, challenging the standard model of membrane electrostatics. The ability of ions to retain their immediate hydration environment, combined with the lack of sensitivity of permeability to ion type or even ion pairs, led us to question the extent to which hydration energetics and electrostatics control membrane ion permeation. Using the arginine analog methyl-guanidinium as a test case, we find that although hydrocarbon electronic polarizability causes dramatic changes in ion solvation free energy, as well as a significant change (approximately 0.4 V) in the membrane dipole potential, little change in membrane permeation energetics occurs. We attribute this to compensation of solvation terms from polar and polarizable nonpolar components within the membrane, and explain why the dipole potential is not fully sensed in terms of the locally deformed bilayer interface. Our descriptions provide a deeper understanding of the translocation process and allow predictions for poly-ions, ion pairs, charged lipids, and lipid flip-flop. We also report simulations of large hydrophobic-ion-like membrane defects and the ionophore valinomycin, which exhibit little membrane deformation, as well as hydrophilic defects and the ion channel gramicidin A, to provide parallels to membranes deformed by unassisted ion permeation.
exocytosis. We analyze these experimental protocols, derive simple formulas for special cases, and distinguish carefully between the Ca2þ current cooperativity, defined as the exponent in the relationship between exocytosis rate and the Ca2þ current magnitude, and the underlying Ca2þ channel cooperativity, defined as the average number of channels involved in the release of a single vesicle. Further, we use 3D computational modeling of buffered Ca2þ diffusion to analyze the distinct Ca2þ cooperativity measures, and demonstrate the role of endogenous Ca2þ buffers on such measures. We show that buffers can either increase or decrease the calcium current cooperativity of exocytosis, depending on their concentration and calcium-binding properties, and the distance between channel and vesicle.
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