A QM/MM study of the molecular recognition site of bapineuzumab toward the amyloid-β peptide isoforms

Abstract

The molecular mechanism of recognition of amyloid-beta (Aβ) peptide isoforms by bapineuzumab was studied using a quantum mechanics and molecular mechanics (QM/MM) method. In this work, geometric optimisations were performed using the ONIOM2 scheme (at B3LYP/6-31G(d) amber)EE level) on the paratope of bapineuzumab together with the different forms of Aβ peptide (AβWT and AβN3(pE)). A comprehensive study of the interactions was also 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 acids of the Aβ peptides. The description on the interactions between bapineuzumab and the different forms of Aβ peptides allow us to understand why the peptides that lack the two first residues (Asp1 and Ala2) and begin with a pyroglutamate residue present low affinity for bapineuzumab. This basic structural information is useful for a deeper understanding about the scope and limitations of bapineuzumab as a therapeutic agent for the AD.