Abstract
In humans, type 1 11β-hydroxysteroid dehydrogenase (11β-HSD-1) plays a key role in the regulation of the glucocorticoids balance by converting the inactive hormone cortisone into cortisol. Numerous functional aspects of 11β-HSD-1 have been understood thanks to the availability at the Worldwide Protein Data Bank of a number of X-ray structures of the enzyme either alone or in complex with inhibitors, and to several experimental data. However at present, a complete description of the dynamic behaviour of 11β-HSD-1 upon substrate binding is missing. To this aim we firstly docked cortisone into the catalytic site of 11β-HSD-1 (both wild type and Y177A mutant), and then we used steered molecular dynamics and metadynamics to simulate its undocking. This methodology helped shedding light at molecular level on the complex relationship between the enzyme and its natural substrate. In particular, the work highlights a) the reason behind the functional dimerisation of 11β-HSD-1, b) the key role of Y177 in the cortisone binding event, c) the fine tuning of the active site degree of solvation, and d) the role of the S228-P237 loop in ligand recognition.
Highlights
Type 1 11b-hydroxysteroid dehydrogenase (11b-HSD-1) is a nicotinamide adenine dinucleotide phosphate (NADPH) dependent enzyme, belonging to the short chain dehydrogenases/ reductases (SDR) superfamily [1,2]
What are the driving forces that come into play? How can enzymes pinpoint partner ligands, either being substrates or inhibitors, within a crowd of possible candidates? What are the thermodynamics consequences of an interaction between a pair of molecules? Even though possible answers can be given based on experimental evidences, the need to have a better understanding on what goes on at a molecular level has prompted researchers, on the one hand, to develop improved force field descriptions [37,38,39,40] to better model molecular interactions, and on the other hand, to deal with physics based computational methods which allow for the accurate mapping of the underpinning energy landscape
Concerning the methodologies employed to enhance the sampling, among other methods, metadynamics has recently shown promising results when challenged with complex biological problems, typically characterised by several degrees of freedom [27,28,41,42]
Summary
Type 1 11b-hydroxysteroid dehydrogenase (11b-HSD-1) is a nicotinamide adenine dinucleotide phosphate (NADPH) dependent enzyme, belonging to the short chain dehydrogenases/ reductases (SDR) superfamily [1,2]. The enzyme is expected to follow a general acid-base mechanism where conserved residues likely important for catalysis comprise S170, Y183, and K187. In the generally accepted reaction model, the tyrosine acts as the catalytic base while the serine helps keeping the substrate in place. The lysine interacts with the NADPH and lowers the pKa of the tyrosine OH, promoting the proton transfer. The hydride transfer is hypothesised to occur from the C4 of the nicotinamide ring to the C11 position of the substrate cortisone (Figure 1) [4,5,6,7]
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