The Use of Multiscale Molecular Simulations in Understanding a Relationship between the Structure and Function of Biological Systems of the Brain: The Application to Monoamine Oxidase Enzymes

Abstract

HIGHLIGHTS Computational techniques provide accurate descriptions of the structure and dynamics of biological systems, contributing to their understanding at an atomic level.Classical MD simulations are a precious computational tool for the processes where no chemical reactions take place.QM calculations provide valuable information about the enzyme activity, being able to distinguish among several mechanistic pathways, provided a carefully selected cluster model of the enzyme is considered.Multiscale QM/MM simulation is the method of choice for the computational treatment of enzyme reactions offering quantitative agreement with experimentally determined reaction parameters.Molecular simulation provide insight into the mechanism of both the catalytic activity and inhibition of monoamine oxidases, thus aiding in the rational design of their inhibitors that are all employed and antidepressants and antiparkinsonian drugs. Aging society and therewith associated neurodegenerative and neuropsychiatric diseases, including depression, Alzheimer's disease, obsessive disorders, and Parkinson's disease, urgently require novel drug candidates. Targets include monoamine oxidases A and B (MAOs), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and various receptors and transporters. For rational drug design it is particularly important to combine experimental synthetic, kinetic, toxicological, and pharmacological information with structural and computational work. This paper describes the application of various modern computational biochemistry methods in order to improve the understanding of a relationship between the structure and function of large biological systems including ion channels, transporters, receptors, and metabolic enzymes. The methods covered stem from classical molecular dynamics simulations to understand the physical basis and the time evolution of the structures, to combined QM, and QM/MM approaches to probe the chemical mechanisms of enzymatic activities and their inhibition. As an illustrative example, the later will focus on the monoamine oxidase family of enzymes, which catalyze the degradation of amine neurotransmitters in various parts of the brain, the imbalance of which is associated with the development and progression of a range of neurodegenerative disorders. Inhibitors that act mainly on MAO A are used in the treatment of depression, due to their ability to raise serotonin concentrations, while MAO B inhibitors decrease dopamine degradation and improve motor control in patients with Parkinson disease. Our results give strong support that both MAO isoforms, A and B, operate through the hydride transfer mechanism. Relevance of MAO catalyzed reactions and MAO inhibition in the context of neurodegeneration will be discussed.

Keywords: central nervous system; computational enzymology; drug design; hydride transfer reaction; molecular dynamics simulation; multiscale simulations; neural signal transduction; neurotransmitter metabolism.

Scheme 1

Overall oxidative deamination of biogenic and dietary amines catalyzed by the MAO enzyme. Amines are enzymatically converted to the corresponding imines, which leave the MAO active site and are non-enzymatically hydrolyzed to aldehydes.

Figure 1

Superposition of FAD and ionisable residues surrounding the active site (MAO A is red, MAO B is blue).

Figure 2

Structures of dopamine (1) and isoalloxazine moiety (2) of the FAD cofactor used in the cluster model of the MAO active site.

Figure 3

Structures of relevant stationary points for the newly proposed two-step MAO catalytic hydride mechanism for the degradation of dopamine 1.

Figure 4

Free-energy profiles for the MAO catalyzed amine degradation reaction initiated by either amino deprotonation (A), or a direct hydride abstraction (B) as obtained with the (CPCM)/M06–2X/6–311++G(2df,2pd)//(CPCM)/M06–2X/6–31+G(d) model employing the cluster model of the enzyme.

Figure 5

Complete two-step mechanism for MAO catalyzed amine degradation. The first step involves H⁻ abstraction from the substrate to form the flavin–substrate adduct, which then decomposes to the final products, namely neutral imine and fully reduced flavin, FADH₂, a reaction promoted by amine deprotonation facilitated by two water molecules.

Figure 6

Structure of the MAO B active site with the reactive neutral dopamine. The FAD prosthetic group is shown in orange, dopamine in light blue, and Lys296 in violet.