caa a22 4500 605512701 CHVBK 20210128100656.0 cr unu---uuuuu 210128e20150401xx s 000 0 eng 10.1007/s00894-015-2620-6 doi (NATIONALLICENCE)springer-10.1007/s00894-015-2620-6 Computational study of missense mutations in phenylalanine hydroxylase [Elektronische Daten] [Kamila Réblová, Petr Kulhánek, Lenka Fajkusová] Hyperphenylalaninemia (HPA) is one of the most common metabolic disorders. HPA, which is transmitted by an autosomal recessive mode of inheritance, is caused by mutations of the phenylalanine hydroxylase gene. Most mutations are missense and lead to reduced protein stability and/or impaired catalytic function. The impact of such mutations varies, ranging from classical phenylketonuria (PKU), mild PKU, to non-PKU HPA phenotypes. Despite the fact that HPA is a monogenic disease, clinical data show that one PKU genotype can be associated with more in vivo phenotypes, which indicates the role of other (still unknown) factors. To better understand the phenotype-genotype relationships, we analyzed computationally the impact of missense mutations in homozygotes stored in the BIOPKU database. A total of 34 selected homozygous genotypes was divided into two main groups according to their phenotypes: (A) genotypes leading to non-PKU HPA or combined phenotype non-PKU HPA/mild PKU and (B) genotypes leading to classical PKU, mild PKU or combined phenotype mild PKU/classical PKU. Combining in silico analysis and molecular dynamics simulations (in total 3μs) we described the structural impact of the mutations, which allowed us to separate 32 out of 34 mutations between groups A and B. Testing the simulation conditions revealed that the outcome of mutant simulations can be modulated by the ionic strength. We also employed programs SNPs3D, Polyphen-2, and SIFT but based on the predictions performed we were not able to discriminate mutations with mild and severe PKU phenotypes. Graphical Abstract The structural impact of the missense mutations with mild and severe phenotypes in the tetrameric structure of the phenylalanine hydroxylase was analyzed using in silico analysis and molecular dynamics simulations. Springer-Verlag Berlin Heidelberg, 2015 Genetic disease nationallicence Hyperphenylalaninemia nationallicence Missense mutation nationallicence In silico tool nationallicence Computer simulation nationallicence Réblová Kamila Central European Institute of Technology (CEITEC), Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic aut Kulhánek Petr Central European Institute of Technology (CEITEC), Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic aut Fajkusová Lenka Central European Institute of Technology (CEITEC), Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic aut Journal of Molecular Modeling Springer Berlin Heidelberg 21/4(2015-04-01), 1-10 1610-2940 21:4<1 2015 21 894 https://doi.org/10.1007/s00894-015-2620-6 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00894-015-2620-6 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Réblová Kamila Central European Institute of Technology (CEITEC), Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic aut NATIONALLICENCE 700 1- Kulhánek Petr Central European Institute of Technology (CEITEC), Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic aut NATIONALLICENCE 700 1- Fajkusová Lenka Central European Institute of Technology (CEITEC), Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic aut NATIONALLICENCE 773 0- Journal of Molecular Modeling Springer Berlin Heidelberg 21/4(2015-04-01), 1-10 1610-2940 21:4<1 2015 21 894