Predicting the functions and specificity of triterpenoid synthases: a mechanism-based multi-intermediate docking approach - PubMed (original) (raw)

Predicting the functions and specificity of triterpenoid synthases: a mechanism-based multi-intermediate docking approach

Bo-Xue Tian et al. PLoS Comput Biol. 2014.

Abstract

Terpenoid synthases construct the carbon skeletons of tens of thousands of natural products. To predict functions and specificity of triterpenoid synthases, a mechanism-based, multi-intermediate docking approach is proposed. In addition to enzyme function prediction, other potential applications of the current approach, such as enzyme mechanistic studies and enzyme redesign by mutagenesis, are discussed.

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Conflict of interest statement

MPJ is a consultant for Schrödinger LLC, which licenses, develops, and distributes software used in this work. All other authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Example structures of TPSs: a) limonene synthase (PDB: 2ONH) ; b) squalene-hopene cyclase (PDB: 1SQC) , .

Figure 2

Figure 2. Example reactions of TPSs: a) limonene synthase; b) squalene-hopene cyclase.

Figure 3

Figure 3. Reaction channels for triterpenoid synthase and triterpenoid synthase-like enzymes , .

Figure 4

Figure 4. Sequence similarity network of triterpenoid synthase and triterpenoid synthase-like proteins colored by reaction channels.

Each node represents a protein sequence, and nodes are connected when the Blast _E_-value for the pair of sequences is more significant than 10−60 (panel a) or 10−220/10−300 (panel b). Gray nodes represent enzymes lacking annotations in the manually curated portion of UniProtKB (Swiss-Prot), i.e., likely to be experimentally uncharacterized.

Figure 5

Figure 5. Illustration of the key dihedral angle C16-C17-C18-H18 that determines the conversion of I1 to I2: a) A-I1; b) B-I1.

Figure 6

Figure 6. Carbocationic intermediate docking scores (MM/GBSA) along the reaction coordinates of a) 1SQC and b) 1W6K.

We arbitrarily assigned a score of +100 kcal/mol to intermediates that could not be successfully docked.

Figure 7

Figure 7. a) Superimposed view of the product lanosterol in the 1W6K crystal structure (grey) and the docking pose of C-I6 (the product precursor carbocation, c.f. Figure 6b ; in orange); b) The docking poses of the second representative intermediates: A-I2 (blue), B-I2 (red) and C-I2 (lime), as well as lanosterol in the 1W6K crystal structure (grey, c.f. Figure 6b ).

Figure 8

Figure 8. Intermediates and products of Channel C.

Figure 9

Figure 9. Docking score (MM/GBSA) of 9 carbocationic intermediates for 22 triterpenoid synthase homology models that follow channel C.

Compounds that could not be successfully docked at all are arbitrarily assigned a docking score of −10 kcal/mol. Figure legend shows the UniProtKB IDs for the triterpenoid synthases. Panel a shows the docking scores against 8 lanosterol synthases (in red); panel b shows the docking scores against 10 cycloartenol synthases (in lime green); and panel c shows the docking scores against a cucurbitadienol synthase (in cyan), a parkeol synthase (in magenta) and 2 protostadienol synthases (in blue). Details c.f. Table S2.

Figure 10

Figure 10. Key intermediates involved in the reaction channel leading to the hopanyl cation (A-I4), and products derived from these.

Figure 11

Figure 11. Example of constraints and restraints used during docking (residue numbering is for 1W6K).

Figure 12

Figure 12. A hypothetical example output of the carbocation docking.

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References

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