Molecular mechanism of recognition of different forms of the amyloid-beta peptide by Bapineuzumab. A QM/MM study.

GUTIÉRREZ LUCAS JOEL; PERUCHENA NELIDA; VETTORAZZI MARCELA; ENRIZ, RICARDO D.

Congreso; 10th Congress of theWorld Association of Theoretical and Computational Chemists (WATOC); 2014

Molecular mechanism of recognition of different forms of the amyloid-b peptide by Bapineuzumab. A QM/MM study.   Lucas J. Gutierrez,a,c Nelida Peruchenac, Marcela C. Vettorazzib and  Ricardo D. Enriz a,b a Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, Chacabuco 915, 5700 San Luis, Argentina; e-mail: lucasgutierrez10@gmail.com; b Instituto Multidisciplinario de Investigaciones Biológicas de San Luis (UNSL-CONICET), Ejercito de Los Andes 950, 5700 San Luis, Argentina; e-mails: denriz@unsl.edu.ar,marcevetto@hotmail.com ; c Laboratorio de Estructura Molecular y Propiedades, Área de Química Física, Departamento de Química, Facultad de Ciencias Exactas y Naturales y Agrimensura, Universidad Nacional del Nordeste. Av. Libertad 5470, Corrientes (3400), Argentina; e-mail: arabeshai@yahoo.com.ar     Alzheimer?s disease (AD) is the most prevalent neurodegenerative disease in humans. It is a genetically complex, slowly progressive, and irreversible neurodegenerative disease of the brain. Currently it is known that amyloid-beta (Ab) peptide form the soluble Ab oligomers, which are key pathogenic structures in AD. The main Ab variants detected in the human brain are N-terminus (AbWT) and N-terminal truncated species (Abn-40/42 where n=2 to 11).   Immunotherapy has become a very attractive alternative as a new treatment for brain disorders. Bapineuzumab is a humanized monoclonal antibody (Mab) that binds with high affinity to the neurotoxic AbWT peptide. However, Bapineuzumab binds the toxic N-terminally modified Ab peptide with loss affinity compared to the AbWT, just as occurs with other antibodies anti-Ab peptide. Thus the question which arises is what is the cause of this different affinity? Actually the problem is that there is no precise information at sub molecular level of the type of molecular interactions that stabilize and / or destabilize these two complexes. It is thus evident that a detailed analysis of the different molecular interactions in the binding process is of paramount importance.   In this work, geometric optimizations were performed using ONIOM2 scheme (at B3LYP/6-31G(d):amber)EE level) on the binding site of Bapineuzumab and the different forms of Ab peptide (AbWT and AbN3(pE)). From the geometries described above a comprehensive study of the interactions was performed through Quantum Theory of Atoms in Molecules (QTAIM). This allowed us to obtain a deep understanding of how this antibody interacts with the amino acid residues of the different Ab peptides.   Our results suggest that the Bapineuzumab has a higher affinity by AbWT compared a AbN3(pE). This is mainly due to the absence of residue Asp1 in AbN3(pE). When this residue is missing the following interactions are lost: Asp1OD1???HGSer101B, Asp1OD2???HSer101B.   This basic structural information can be useful for a deeper understanding about the scope and limitations of Bapineuzumab as a therapeutically agent for the AD. On the other hand this information might be also useful to improve the therapeutically effect of novel monoclonal antibodies anti-Ab peptide.   Acknowledgments: Universidad Nacional de San Luis, Universidad Nacional del Nordeste and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET).