DNA methylation plays key roles in mammalian cells and is modulated by a set of proteins which recognize symmetrically methylated nucleotides. Among them, the protein MECP2 shows multifunctional roles repressing and/or activating genes by binding to both methylated and unmethylated regions of the genome. The interest for this protein markedly increased from the observation that its mutations are the primary cause of Rett syndrome, a neurodevelopmental disorder which causes mental retardation in young females. Thus, the present study is aimed to investigate the effects of some of these known pathogenic missense mutations (i.e. R106Q, R106W, R111G, R133C and R133H) on the MECP2 folding and DNA binding by molecular dynamics simulations. The effects of the simulated mutations are also parameterized by using a here proposed new tool, named Rescore+, implemented in the VEGA ZZ suite of programs, which calculates a set of scoring functions on all frames of a trajectory or on all complexes contained in a database thus allowing an easy rescoring of results coming from MD or docking simulations. The obtained results revealed that the reported loss of the MECP2 function induced by the simulated mutations can be ascribed to both stabilizing and destabilizing effect on DNA binding. The study confirms that MD simulations are particularly useful to rationalize and predict the mutation effects offering insightful information for diagnostics and drug design.

Structural Effects of Some Relevant Missense Mutations on the MECP2-DNA Binding : a MD Study Analyzed by Rescore+, a Versatile Rescoring Tool of the VEGA ZZ Program / A. Pedretti, C. Granito, A. Mazzolari, G. Vistoli. - In: MOLECULAR INFORMATICS. - ISSN 1868-1743. - 35:8-9(2016), pp. 424-433. [10.1002/minf.201501030]

Structural Effects of Some Relevant Missense Mutations on the MECP2-DNA Binding : a MD Study Analyzed by Rescore+, a Versatile Rescoring Tool of the VEGA ZZ Program

A. Pedretti
Primo
;
A. Mazzolari
Penultimo
;
G. Vistoli
2016

Abstract

DNA methylation plays key roles in mammalian cells and is modulated by a set of proteins which recognize symmetrically methylated nucleotides. Among them, the protein MECP2 shows multifunctional roles repressing and/or activating genes by binding to both methylated and unmethylated regions of the genome. The interest for this protein markedly increased from the observation that its mutations are the primary cause of Rett syndrome, a neurodevelopmental disorder which causes mental retardation in young females. Thus, the present study is aimed to investigate the effects of some of these known pathogenic missense mutations (i.e. R106Q, R106W, R111G, R133C and R133H) on the MECP2 folding and DNA binding by molecular dynamics simulations. The effects of the simulated mutations are also parameterized by using a here proposed new tool, named Rescore+, implemented in the VEGA ZZ suite of programs, which calculates a set of scoring functions on all frames of a trajectory or on all complexes contained in a database thus allowing an easy rescoring of results coming from MD or docking simulations. The obtained results revealed that the reported loss of the MECP2 function induced by the simulated mutations can be ascribed to both stabilizing and destabilizing effect on DNA binding. The study confirms that MD simulations are particularly useful to rationalize and predict the mutation effects offering insightful information for diagnostics and drug design.
DNA binding; MECP2; Missense mutations; Molecular dynamics; Rescoring tool; Molecular Medicine; Structural Biology; Organic Chemistry; Computer Science Applications1707 Computer Vision and Pattern Recognition; Drug Discovery3003 Pharmaceutical Science
Settore CHIM/08 - Chimica Farmaceutica
2016
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/451504
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