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Molecular Dynamics study of the effect of Multi‐target Compounds binding onto BACE1
Author(s) -
Zahran Mai,
Guevara Johnny,
Martinez Alberto
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.lb39
Subject(s) - allosteric regulation , ligand (biochemistry) , amyloid precursor protein , chemistry , amyloid beta , transmembrane protein , molecular dynamics , peptide , biophysics , biochemistry , stereochemistry , enzyme , alzheimer's disease , biology , medicine , computational chemistry , receptor , disease , pathology
Alzheimer's disease (AD), discovered over a hundred years ago, is a fatal progressive neurodegenerative disease that is the most common form of dementia. The symptoms of AD are hypothesized to be due the accumulation of amyloid beta (AB) peptides. The amyloid precursor protein (APP) is an integral membrane protein present on the surface of nerve cells that contains the AB peptide sequence. Cleavage of APP by a transmembrane aspartyl protease known as the beta‐site APP cleaving enzyme 1 (BACE1) and gamma secretase lead to AB peptide deposits of varying neurotoxic isoforms in the surrounding extracellular fluid. In this study we are using molecular dynamics (MD) simulation to observe the dynamical behavior of BACE1 after ligand binding. We are investigating six ligands that have been shown to bind and reduce the activity of BACE1. Our results show a correlation between ligand toxicity and conformational flexibility of the BACE1‐ligand complex. Additionally, we investigated the potential allosteric effect of ligand binding on different sites than the catalytic site. Consideration of conformational dialogue between allosteric ligands and protein conformations should be considered for the design of future drugs targeting BACE1. Support or Funding Information The author(s) are grateful to the Center for Theoretical Physics of New York City College of Technology for providing computational resources.Electrostatic surface representation of BACE1 bound to 6 multi‐compound ligands.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .