In silico screening and molecular dynamics simulation of deleterious PAH mutations responsible for phenylketonuria genetic disorder.
Andrea LopezBrandon HavranekGeorge A PapadantonakisShahidul M IslamPublished in: Proteins (2021)
Phenylketonuria (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.
Keyphrases
- molecular dynamics
- polycyclic aromatic hydrocarbons
- density functional theory
- molecular dynamics simulations
- genome wide
- molecular docking
- copy number
- mental health
- end stage renal disease
- protein protein
- binding protein
- transcription factor
- chronic kidney disease
- newly diagnosed
- emergency department
- monte carlo
- amino acid
- gene expression
- prognostic factors
- peritoneal dialysis
- small molecule
- dna binding
- wild type
- genome wide analysis
- network analysis