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posted on 2023-01-10, 22:58 authored by Andrea Lopez, Brandon Havranek, George PapadantonakisGeorge Papadantonakis, Mohammad IslamMohammad IslamPhenylketonuria (PKU) is a genetic disorder that if left untreated can lead to behavioral problems, epilepsy, and even mental retardation. PKU results from mutations within the phenylalanine-4-hydroxylase (PAH) gene that encodes for the PAH protein. The study of all PAH causing mutations is improbable using experimental techniques. In this study, a collection of in silico resources, sorting intolerant from tolerant, Polyphen-2, PhD-SNP, and MutPred were used to identify possible pathogenetic and deleterious PAH non-synonymous single nucleotide polymorphisms (nsSNPs). We identified two variants of PAH, I65N and L311P, to be the most deleterious and disease causing nsSNPs. Molecular dynamics (MD) simulations were carried out to characterize these point mutations on the atomic level. MD simulations revealed increased flexibility and a decrease in the hydrogen bond network for both mutants compared to the native protein. Free energy calculations using the MM/GBSA approach found that BH4, a drug-based therapy for PKU patients, had a higher binding affinity for I65N and L311P mutants compared to the wildtype protein. We also identify important residues in the BH4 binding pocket that may be of interest for the rational drug design of other PAH drug-based therapies. Lastly, free energy calculations also determined that the I65N mutation may impair the dimerization of the N-terminal regulatory domain of PAH.
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Citation
Lopez, A., Havranek, B., Papadantonakis, G. A.Islam, S. M. (2021). In silico screening and molecular dynamics simulation of deleterious PAH mutations responsible for phenylketonuria genetic disorder. Proteins: Structure, Function and Bioinformatics, 89(6), 683-696. https://doi.org/10.1002/prot.26051Publisher
WileyLanguage
enissn
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Keywords
free energy calculationsin silico genetic screeningmolecular dynamicsPKU variantstetrahydrobiopterinGeneticsRare Diseases2 Aetiology2.1 Biological and endogenous factors3 Good Health and Well BeingBinding SitesBiopterinCoenzymesDrug DesignGene ExpressionHumansHydrogen BondingKineticsMolecular Dynamics SimulationPhenylalanine HydroxylasePhenylketonuriasPoint MutationPolymorphism, Single NucleotideProtein BindingProtein Conformation, alpha-HelicalProtein Conformation, beta-StrandProtein Interaction Domains and MotifsProtein MultimerizationSubstrate SpecificityThermodynamicsBioinformaticsMathematical SciencesBiological SciencesInformation and Computing Sciences