Abstract

CRUZ-JIMENEZ, Juan Carlos; MERCADO-MONTOYA, Marcela; OSTOS-ORTIZ, Carlos Eduardo  and  HERNANDEZ-VALDIVIESO, Alher Mauricio. Molecular dynamics simulations of Alzheimer's BACE1 and BACE2 transmembrane domains in neurons: Impact of cholesterol. Rev.fac.ing.univ. Antioquia [online]. 2021, n.98, pp.117-128. ISSN 0120-6230.  https://doi.org/10.17533/udea.redin.20200368.

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.

Keywords : Modal analysis; complex modes; structural analysis; molecular interaction.

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