Small-size peptides acting as inhibitors of the BACE1-exosite. A molecular modeling study using MD simulations, QM calculations and QTAIM analysis

GUTIERREZ,LUCAS ; ANGELINA, EMILIO; PERUCHENA, N. M.; BALDONI, H. ; ENRIZ, D. R.

Santiago de Chile

Congreso; 10th Congress of the World Association of Theoretical and Computational Chemits; 2014

World Association of Theoretical and Computational Chemits...

 Alzheimer´s disease (AD) is the most common form of dementia affecting 6-10% of people over the age of 65 [1]. Several possible molecular mechanisms may initiate AD. The most widely accepted theory regarding the etiology of AD is known as the ?amyloid hypothesis? which features the amyloid b-peptide (Ab) as the central pathological agent. This hypothesis posits that pathology initiates because of an imbalance in Ab production and/or clearance, which may result from altered expression or processing of amyloid precursor protein (APP)[2]. The aspartyl protease b-site APP cleaving enzyme 1 (BACE1) is the primary b-secretase in the brain, making it a prime candidate for AD therapeutics.   A molecular modeling study on small-size peptides possessing inhibitory effect against BACE1 was carried out. By combining Molecular Dynamics (MD) simulations with ab initio and Density Functional Theory (DFT) calculations, a simple and generally applicable procedure to evaluate the binding energies of small-size peptides interacting with the BACE1-exosite binding site is reported here. The structural aspects obtained for the different complexes were analyzed providing a clear picture about the binding interactions of these peptides from both structural and energetic points of view. Molecular aspects of the binding interactions between these peptides and the BACE1-exosite are discussed in details. Additionally, we report about the results obtained by charge density analysis of the network of non covalent interactions established in the exosite of BACE1, by formation of complexes with small-size peptides acting as inhibitors. These interactions have been investigated within the framework of the DFT and the Quantum Theory of Atoms in Molecules (QTAIM) using a reduced model. Although the approach used here was traditionally applied to the study of non covalent interactions in small molecules complexes in gas phase, we show through in this work that this methodology is also a very powerful tool for the study of biomolecular complexes, providing a very detailed description of the binding event of peptides inhibitors at the exosite of BACE1.   Acknowledgments: Authors  acknowledges Universidad Nacional de San Luis, Universidad Nacional del Nordeste and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET).  References:  [1] A.B. Clippingdale, J.D. Wade, C.J. Barrow, J. Pept. Sci. 7 (2001) 227. [2] J. Hardy, D.J. Selkoe, Science. 297 (2002) 353.