A molecular dynamics study of the BACE1 conformational change from Apo to closed form induced by hydroxyethylamine derived compounds

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• 作者：Carlos Gueto-Tettay ; Joshua Zuchniarz ; Yeyson Fortich-Seca ; Luis Roberto Gueto-Tettay ; Juan Carlos Drosos-Ramirez ; ^{jdrososr@unicartagena.edu.co}
• 关键词：Alzheimer&rsquo ; s disease ; Hydroxyethylamines ; GROMACS ; BACE1 ; Flap ; Population density
• 刊名：Journal of Molecular Graphics and Modelling
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：70
• 期：Complete
• 页码：181-195
• 全文大小：5805 K
• 卷排序：70

文摘

The dynamics of the flap are fundamental to the catalytic function of the enzyme. When BACE1 is inactive (Apo), the flap adopts an open conformation, allowing a substrate or inhibitor to access the active site. Subsequent interaction with the ligand induces flap closure and stabilization. The protonation state of the aspartic dyad is affected by the chemical nature of ligand. Appropriate selection of protonation states for each component is significant for simulation. The configuration of protonation state that induces the change from the Apo to closed form of BACE1 by HEAs is the LnAsp289 (Neutral form of the ligand and the protonated form of the Asp 289). The protonation of the ligand occurs inside the active site of the protein and is an event subsequent to the closing of the flap. Activity of HEAs depends mainly on the capacity to establish and maintain interactions during the time with residues such as Asp93, Gly95, Thr133, Asp289, Gly291, and Asn294. This step allows differentiation among the inhibitory activities of the HEAs. The population density concept is an efficient tool to evaluate from different protonation conformational options and could be used to evaluate other systems subject to simultaneous protonation of ligand and protein issues.