Molecular Dynamics-Assisted Interaction of Vanadium Complex–AMPK: From Force Field Development to Biological Application for Alzheimer’s Treatment

Abstract

A large part of the world’s population is affected by Alzheimer’s disease (AD) and diabetes mellitus type 2, which cause both social and economic impacts. These two conditions are associated with one protein, AMPK. Studies have shown that vanadium complexes, such as bis(N′,N′-dimethylbiguanidato)-oxovanadium(IV), VO(metf)2·H2O, are potential agents against AD. A crucial step in drug design studies is obtaining information about the structure and interaction of these complexes with the biological targets involved in the process through molecular dynamics (MD) simulations. However, MD simulations depend on the choice of a good force field that could present reliable results. Moreover, general force fields are not efficient for describing the properties of metal complexes, and a VO(metf)2·H2O-specific force field does not yet exist; thus, the proper development of a parameter set is necessary. Furthermore, this investigation is essential and relevant given the importance for both the scientific community and the population that is affected by this neurodegenerative disease. Therefore, the present work aims to develop and validate the AMBER force field parameters for VO(metf)2·H2O since the literature lacks such information on metal complexes and investigate through classical molecular dynamics the interactions made by the complex with the protein. The proposed force field proved to be effective for describing the vanadium complex (VC), supported by different analyses and validations. Moreover, it had a great performance when compared to the general AMBER force field. Beyond that, MD findings provided an in-depth perspective of vanadium complex–protein interactions that should be taken into consideration in future studies.

Evaluation of autophagy inhibition to combat cancer: (vanadium complex)–protein interactions, parameterization, and validation of a new force field

“…Nevertheless, one of the biggest challenges in performing MD simulations to investigate the behavior of ligands with their molecular targets is to use a force field that satisfactorily reproduces the properties of interest [ 73 ]. In the case of metal complexes, the difficulty increases significantly [ 55 , 74 ].…”

Evaluation of autophagy inhibition to combat cancer: (vanadium complex)–protein interactions, parameterization, and validation of a new force field

“…Nevertheless, one of the biggest challenges in performing MD simulations to investigate the behavior of ligands with their molecular targets is to use a force field that satisfactorily reproduces the properties of interest [73]. In the case of metal complexes, the difficulty increases significantly [68,85].…”

MD Simulations to Calculate NMR Relaxation Parameters of Vanadium(IV) Complexes: A Promising Diagnostic Tool for Cancer and Alzheimer’s Disease

“…Furthermore, recent studies have been conducted to investigate the use of VCs as promising candidates for the treatment of COVID-19 due to their antiviral, anti-inflammatory, and hypoglycemic effects [35][36][37]. Recently, VCs such as [VO(metf) 2 ]•H 2 O (VC1) and [VO(bpy) 2 Cl] + (VC2), where metf is metformin and bpy is bipyridine, have shown great potential regarding their application to AD and autophagy associated with triple-negative breast cancer, respectively [38,39].…”

“…In the study conducted by Tavares et al [38], the biological application of VC1 in the system containing AMP-activated protein kinase (AMPK) was investigated. AMPK plays a pivotal role in AD and is considered a link between AD and diabetes mellitus type 2.…”

“…Moreover, allying MD simulation with less expensive quantum methods (QM) can be very useful to reduce the computational demand and assess NMR properties, which is not computationally feasible using robust QM calculation [40][41][42]. Therefore, in order to ensure correct results and a feasible calculation, previous works [38,39] parametrized a force field for VC1 and VC2, where relevant relativistic effects were also taken into account. Thus, with the presented background, MD simulations could be carried out.…”