Molecular dynamics simulations of Alzheimer's BACE1 and BACE2 transmembrane domains in neurons: Impact of cholesterol

ABSTRACT : Molecular dynamic (MD) simulation is an approach frequently employed in computational biology for exhaustive sampling of the protein-ligand conformational space. Hence, it is useful for structural analysis and the study of molecular interactions. In this study, we report on a MD simulation protocol to understand the dynamics of β-secretase 1 (BACE1) and 2 (BACE2), widely known to play a critical role in the etiology of Alzheimer’s disease, by a structure change evaluation of their transmembrane domains while inserted in a simulated neural membrane system. We considered two different levels in membrane cholesterol content. Because there is no evidence supporting the capacity of BACE1 and BACE2 to exist as a dimer, single and double (BACE1/BACE1, BACE2/BACE2, BACE1/BACE2) systems, either in parallel or antiparallel orientation, were prepared for each run. Analysis of tridimensional structure of BACE1 and BACE2, after 10ns of MD simulation, revealed a correlation between higher cholesterol levels and both peptide refolding and changes in the secondary structure of both transmembrane domains in single and double systems. Interestingly, our results also indicate a potential interaction in the double system BACE2/BACE2, particularly when the domains had an antiparallel orientation.

• Autores: Cruz Jiménez, Juan Carlos; Mercado Montoya, Marcela; Ostos Ortíz, Carlos Eduardo; Hernández Validivieso, Alher Mauricio
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2021
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/24961
• Acceso en línea: http://hdl.handle.net/10495/24961; https://revistas.udea.edu.co/index.php/ingenieria/article/view/332882
• Palabra clave: Enfermedad de Alzheimer; Alzheimer Disease; Colesterol; Cholesterol; Análisis modal; Modos complejos; Análisis estructural; Interacción molecular
• Rights: openAccess
• License: http://creativecommons.org/licenses/by-nc-sa/2.5/co/