How does excess phenylalanine affect the packing density and fluidity of a lipid membrane?

Literature Information

Publication Date 2021-11-16
DOI 10.1039/D1CP05004D
Impact Factor 3.676
Authors

Shakkira Erimban, Snehasis Daschakraborty


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Abstract

Phenylketonuria (PKU) is an autosomal recessive error of phenylalanine (Phe) metabolism, where untreated Phe becomes cytotoxic. Previous experiments found that excess Phe decreases the packing density and increases the fluidity and permeability of a lipid membrane. It was proposed that Phe forms cytotoxic nanoscopic amyloid-like fibrils. In another study, the Phe fibrils were not visible near the lipid membrane. So, what leads to the deleterious effect of Phe on the lipid membrane? We put forward a molecular mechanism for the observed effect of excess Phe on the lipid membrane using all-atom molecular dynamics simulation. This study suggests that Phe monomers spontaneously intercalate into the membrane and form small hydrogen-bonded clusters, some of which locally perturb the membrane. These local effects result in an overall reduction in the membrane packing density, enhancement of membrane fluidity, and an increase of water permeability, observed in experiments. The present study does not observe any effect of the nanoscopic fibrillar structure of Phe on the membrane. This study, therefore, provides alternative insights into the excess Phe cytotoxicity in PKU disease.

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Physical Chemistry Chemical Physics
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