Holland, Bryan W.; Berry, Mark D.; Gray, C. G.; Tomberli, Bruno
A Permeability Study of O-2 and the Trace Amine p-Tyramine through Model Phosphatidylcholine Bilayers
PLOS ONE, 10 Art. No. e0122468, JUN 18 2015

We study here the permeability of the hydrophobic O-2 molecule through a model DPPC bilayer at 323K and 350K, and of the trace amine p-tyramine through PC bilayers at 310K. The tyramine results are compared to previous experimental work at 298K. Nonequilibrium work methods were used in conjunction to simultaneously obtain both the potential of mean force (PMF) and the position dependent transmembrane diffusion coefficient, D(z), from the simulations. These in turn were used to calculate the permeability coefficient, P, through the inhomogeneous solubility-diffusion model. The results for O-2 are consistent with previous simulations, and agree with experimentally measured P values for PC bilayers. A temperature dependence in the permeability of O-2 through DPPC was obtained, with P decreasing at higher temperatures. Two relevant species of p-tyramine were simulated, from which the PMF and D(z) were calculated. The charged species had a large energetic barrier to crossing the bilayer of similar to 21 kcal/mol, while the uncharged, deprotonated species had a much lower barrier of similar to 7 kcal/mol. The effective in silico permeability for p-tyramine was calculated by applying three approximations, all of which gave nearly identical results (presented here as a function of the pK(a)). As the permeability value calculated from simulation was highly dependent on the pK(a) of the amine group, a further pK(a) study was performed that also varied the fraction of the uncharged and zwitterionic p-tyramine species. Using the experimental P value together with the simulated results, we were able to label the phenolic group as responsible for the pK(a1) and the amine for the pK(a2), that together represent all of the experimentally measured pK(a) values for p-tyramine. This agrees with older experimental results, in contrast to more recent work that has suggested there is a strong ambiguity in the pK(a) values.


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