Natural products are an abundant source for novel structures and bioactivities. However, the biosynthetic gene clusters (BGCs) that produce them are often cryptic. The TetR family of transcription factors are known to be involved in the suppression of BGCs and have been found to interact with gamma-butyrolactones (GBLs) to induce a conformational change responsible for reduced binding affinity towards its DNA binding site. Herein, we describe the use of molecular dynamics (MD) simulations to better understand how various GBLs interact within the ligand binding site of ScbR, a member of the TetR family. Specifically, we examine the conformational dynamics in various ScbR-GBL systems to elucidate which GBLs are capable of inducing the conformational change responsible for release from DNA. From our simulations of ScbR with GBLs such as A-factor, SCBs 1-8, and VBs A-E, we found that correlated motions within a network of hydrophobic residues linking helices 1,4,6, and 7 may indicate induction of ScbR.

Molecular dynamics to gain insight on ScbR induction by gamma-butyrolactone signaling molecules

ACS Spring 2022

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