Small-size peptides acting as inhibitors of the BACE1-exosite. A mole-cular modeling study using MD simulations and QM calculations

L.GUTIERREZ; E. ANGELINA; N.PERUCHENA; H. BALDONI; ENRIZ R D

Santiago

Congreso; WATOC; 2014

A molecular modeling study on small-size peptides possessing inhibitory effect against -site Amyloid precursor protein Cleaving Enzyme 1 (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.