Binding Modes and Metabolism of Caffeine.

Abstract:

:A correct estimate of ligand binding modes and a ratio of their occupancies is crucial for calculations of binding free energies. The newly developed method BLUES combines molecular dynamics with nonequilibrium candidate Monte Carlo. Nonequilibrium candidate Monte Carlo generates a plethora of possible binding modes and molecular dynamics enables the system to relax. We used BLUES to investigate binding modes of caffeine in the active site of its metabolizing enzyme Cytochrome P450 1A2 with the aim of elucidating metabolite-formation profiles at different concentrations. Because the activation energies of all sites of metabolism do not show a clear preference for one metabolite over the others, the orientations in the active site must play a key role. In simulations with caffeine located in a spacious pocket above the I-helix, it points N3 and N1 to the heme iron, whereas in simulations where caffeine is in close proximity to the heme N7 and C8 are preferably oriented toward the heme iron. We propose a mechanism where at low caffeine concentrations caffeine binds to the upper part of the active site, leading to formation of the main metabolite paraxanthine. On the other hand, at high concentrations two molecules are located in the active site, forcing one molecule into close proximity to the heme and yielding metabolites theophylline and trimethyluretic acid. Our results offer an explanation of previously published experimental results.

journal_name

Chem Res Toxicol

authors

Jandova Z,Gill SC,Lim NM,Mobley DL,Oostenbrink C

doi

10.1021/acs.chemrestox.9b00030

subject

Has Abstract

pub_date

2019-07-15 00:00:00

pages

1374-1383

issue

7

eissn

0893-228X

issn

1520-5010

journal_volume

32

pub_type

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