title: Molecular Dynamics Approach in the Comparison of Wild-Type and Mutant Paraoxonase-1 Apoenzyme Form.
abstract: There is some evidence linking the mammalian paraoxonase-1 (PON1) loops (L1 and L2) to an increased flexibility and reactivity of its active site with potential substrates. The aim of this work is to study the structural, dynamical, and functional effects of the most flexible regions close to the active site and to determine the impact of mutations on the protein. For both models, wild-type (PON1wild) and PON1 mutant (PON1mut) models, the L1 loop and Q/R and L/M mutations were constructed using MODELLER software. Molecular dynamics simulations of 20 ns at 300 K on fully modeled PON1wild and PON1mut apoenzyme have been done. Detailed analyses of the root-mean-square deviation and fluctuations, H-bonding pattern, and torsion angles have been performed. The PON1wild results were then compared with those obtained for the PON1mut. Our results show that the active site in the wild-type structure is characterized by two distinct movements of opened and closed conformations of the L1 and L2 loops. The alternating and repetitive movement of loops at specific times is consistent with the presence of 11 defined hydrogen bonds. In the PON1mut, these open-closed movements are therefore totally influenced and repressed by the Q/R and L/M mutations. In fact, these mutations seem to impact the PON1mut active site by directly reducing the catalytic core flexibility, while maintaining a significant mobility of the switch regions delineated by the loops surrounding the active site. The impact of the studied mutations on structure and dynamics proprieties of the protein may subsequently contribute to the loss of both flexibility and activity of the PON1 enzyme.
authors.affiliation: Laboratoire de Biologie et Santé (URAC34), Département de Biologie, Faculté des Sciences Ben Msik, Université Hassan II de Casablanca, Maroc.
authors.forename: Khadija
authors.initials: K
authors.lastname: Amine
authors.affiliation: Laboratoire de Biologie et Santé (URAC34), Département de Biologie, Faculté des Sciences Ben Msik, Université Hassan II de Casablanca, Maroc.
authors.forename: Lamia
authors.initials: L
authors.lastname: Miri
authors.affiliation: l'Association Marocaine pour la Promotion du Logiciel Libre (AMP2L), Maroc.
authors.forename: Adil
authors.initials: A
authors.lastname: Naimi
authors.affiliation: Laboratoire de Biologie et Santé (URAC34), Département de Biologie, Faculté des Sciences Ben Msik, Université Hassan II de Casablanca, Maroc.
authors.forename: Rachid
authors.initials: R
authors.lastname: Saile
authors.affiliation: Laboratoire de Mathématiques Appliquées et Systèmes d'Informations, Département de Mathématiques, Physique et Informatique, Faculté Pluridisciplinaire de Nador, Université Mohammed Premier, Oujda, Maroc. ; Grille Nationale de Calcul au Centre National de la Recherche Scientifique et Technique, Rabat, Maroc.
authors.forename: Abderrahmane
authors.initials: A
authors.lastname: El Kharrim
authors.affiliation: Laboratoire de Géosciences Appliquées à l'Ingénierie de l'Aménagement, Département de Chimie, Faculté des Sciences Ain Chock, Université Hassan II, Casablanca, Maroc.
authors.forename: Afaf
authors.initials: A
authors.lastname: Mikou
authors.affiliation: Laboratoire de Biologie et Santé (URAC34), Département de Biologie, Faculté des Sciences Ben Msik, Université Hassan II de Casablanca, Maroc.
authors.forename: Anass
authors.initials: A
authors.lastname: Kettani
keywords: PON1; molecular dynamics; mutation; simulation