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A Permeability Study of O2 and the Trace Amine p-Tyramine through Model Phosphatidylcholine Bilayers.

Holland BW, Berry MD, Gray CG, Tomberli B - PLoS ONE (2015)

Bottom Line: The tyramine results are compared to previous experimental work at 298K.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 pKa).This agrees with older experimental results, in contrast to more recent work that has suggested there is a strong ambiguity in the pKa values.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada; Department of Physics, University of Guelph, Guelph, Ontario, Canada.

ABSTRACT
We study here the permeability of the hydrophobic O2 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 O2 are consistent with previous simulations, and agree with experimentally measured P values for PC bilayers. A temperature dependence in the permeability of O2 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 ~ 21 kcal/mol, while the uncharged, deprotonated species had a much lower barrier of ~ 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 pKa). As the permeability value calculated from simulation was highly dependent on the pKa of the amine group, a further pKa 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 pKa1 and the amine for the pKa2, that together represent all of the experimentally measured pKa 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 pKa values.

No MeSH data available.


Related in: MedlinePlus

Snapshots of the tyramine/POPC systems, with tyramine near the bilayer center.(A) The unprotonated tyr permeates without any water accompaniment, and with no obvious orientational preference. (B) The protonated tyr+ never loses the solvation shell around the amine group, and as such always orients along its long axis with the phenolic group leading and the amine trailing. For a more detailed orientation analysis, see [54].
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pone.0122468.g003: Snapshots of the tyramine/POPC systems, with tyramine near the bilayer center.(A) The unprotonated tyr permeates without any water accompaniment, and with no obvious orientational preference. (B) The protonated tyr+ never loses the solvation shell around the amine group, and as such always orients along its long axis with the phenolic group leading and the amine trailing. For a more detailed orientation analysis, see [54].

Mentions: For bilayer interaction, appropriate orientational sampling is justified in a different manner. By allowing the tyramine to orient randomly each time it approached the bilayer in the ten separate simulations, we were able to sample over a wider array of incoming orientations. Although due to its large dipole, tyr+ tended to orient itself in a similar manner each time it approached the bilayer, regardless of the original randominized orientation (see Fig 3). The sampling was also helped by using a larger oscillation amplitude of 2.5 Å, forcing the molecule to interact with portions of the bilayer, and then retreat sufficiently to allow for a change in orientation the next time it came into contact with the bilayer. This kept the molecule from becoming stuck in a particular orientation with a metastable energy, a very common problem for sampling in equilibrium based methods. Finally, there exists a highly probable orientation for tyr+ within the bilayer [54] and so it is assumed that the most relevant portions of the orientational phase space have been sampled.


A Permeability Study of O2 and the Trace Amine p-Tyramine through Model Phosphatidylcholine Bilayers.

Holland BW, Berry MD, Gray CG, Tomberli B - PLoS ONE (2015)

Snapshots of the tyramine/POPC systems, with tyramine near the bilayer center.(A) The unprotonated tyr permeates without any water accompaniment, and with no obvious orientational preference. (B) The protonated tyr+ never loses the solvation shell around the amine group, and as such always orients along its long axis with the phenolic group leading and the amine trailing. For a more detailed orientation analysis, see [54].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4472697&req=5

pone.0122468.g003: Snapshots of the tyramine/POPC systems, with tyramine near the bilayer center.(A) The unprotonated tyr permeates without any water accompaniment, and with no obvious orientational preference. (B) The protonated tyr+ never loses the solvation shell around the amine group, and as such always orients along its long axis with the phenolic group leading and the amine trailing. For a more detailed orientation analysis, see [54].
Mentions: For bilayer interaction, appropriate orientational sampling is justified in a different manner. By allowing the tyramine to orient randomly each time it approached the bilayer in the ten separate simulations, we were able to sample over a wider array of incoming orientations. Although due to its large dipole, tyr+ tended to orient itself in a similar manner each time it approached the bilayer, regardless of the original randominized orientation (see Fig 3). The sampling was also helped by using a larger oscillation amplitude of 2.5 Å, forcing the molecule to interact with portions of the bilayer, and then retreat sufficiently to allow for a change in orientation the next time it came into contact with the bilayer. This kept the molecule from becoming stuck in a particular orientation with a metastable energy, a very common problem for sampling in equilibrium based methods. Finally, there exists a highly probable orientation for tyr+ within the bilayer [54] and so it is assumed that the most relevant portions of the orientational phase space have been sampled.

Bottom Line: The tyramine results are compared to previous experimental work at 298K.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 pKa).This agrees with older experimental results, in contrast to more recent work that has suggested there is a strong ambiguity in the pKa values.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada; Department of Physics, University of Guelph, Guelph, Ontario, Canada.

ABSTRACT
We study here the permeability of the hydrophobic O2 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 O2 are consistent with previous simulations, and agree with experimentally measured P values for PC bilayers. A temperature dependence in the permeability of O2 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 ~ 21 kcal/mol, while the uncharged, deprotonated species had a much lower barrier of ~ 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 pKa). As the permeability value calculated from simulation was highly dependent on the pKa of the amine group, a further pKa 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 pKa1 and the amine for the pKa2, that together represent all of the experimentally measured pKa 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 pKa values.

No MeSH data available.


Related in: MedlinePlus