In silico analyses of the effects of a point mutation and a pharmacological chaperone on the thermal fluctuation of phenylalanine hydroxylase

- The structural flexibility of PAH is increased by the point mutation A313T.
- The increase in flexibility of the PAH mutant decreases its enzymatic activity.
- Binding to a pharmacological chaperone stabilizes the mutant PAH.
- The enhanced stabilization contributes to restoring enzymatic activity.

Phenylketonuria (PKU) is an inborn error of phenylalanine metabolism due to mutations in phenylalanine hydroxylase (PAH). Recently, small compounds, known as pharmacological chaperones (PhCs), have been identified that restore the enzymatic activity of mutant PAHs. Understanding the mechanism of the reduction in enzymatic activity due to a point mutation in PAH and its restoration by PhC binding is important for the design of more effective PhC drugs. Thermal fluctuations of an enzyme can alter its activity. Here, molecular dynamics simulation show the thermal fluctuation of PAH is increased by introduction of the A313T mutation. Moreover, a simulation using the A313T-PhC complex model was also performed. Thermal fluctuation of the mutant was found to be reduced upon PhC binding, which contributes to restoring its enzymatic activity.

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