Probing interactions between vanadium complexes and potential targets for Alzheimer's treatment: parameterization of a new amber force field and biological applications

Abstract

Alzheimer's disease (AD) affects a large part of the world population, with social and economic impacts. One of the etiological hypotheses proposes that there is a link between AD and type 2 diabetes mellitus (T2DM), even though the mechanism is yet to be unraveled. Studies show that vanadium complexes, such as the BMOV and VO(metf)2·H2O, are potential agents against this neurodegenerative disorder. Thus, Molecular Dynamics (MD) simulations are advantageous for obtaining information about the structures and interactions of these complexes with the biological targets involved in the process, namely AMPK and PTP1B. However, DMs are dependent on the choice of a good force field. Therefore, the present work aims to develop AMBER force field parameters for BMOV and VO(metf)2·H2O, since the literature lacks such information on metal complexes. From quantum-mechanical calculations, the global minimum energy structures were found, with theory level B3LYP/def2-TZVP plus ECP for the vanadium atom. RESP charges and Hessian matrix calculations were performed using the same functional and basis set. The values of force constants were obtained by diagonalizing the Hessian matrix and the Lennard-Jones parameters were assigned based on GAFF, for all atoms except vanadium. In order to validate the developed force fields, MD simulations in vacuum and room temperature were carried out. After that, MDs were performed in order to acquire information about relevant interactions between vanadium complexes and the proteins associated to AD. The new models developed and reported by this work showed to be efficient to describe the molecules under study, when compared to experimental data and to quantum references. Furthermore, great insights about the behavior of the systems, such as relevant residues that interact with BMOV and VO(metf)2·H2O are reported. It is expected that this work may assist to motivate future work involving vanadium complexes for the treatment AD.