Stereoselective disulfide formation stabilizes the local peptide conformation in nisin mimics.
Nisin is a polymacrocyclic peptide antimicrobial with high activity against Gram-positive bacteria. Lanthionine and methyllanthionine bridges, closing the macrocycles, are stabilized by thioether bonds, formed between cysteines and dehydrated serine or threonine. The role of polypeptide backbone conformation in the formation of macrocycles A and B within cysteine mutants of nisin residues 1−12 is investigated here by molecular dynamics simulations. Enantiomeric combinational space of Cys3 and Cys7 and of Cys8 and Cys11 is examined for the preference of disulfide bond formation over helical turn formation within this region. A clear preference for spontaneous disulfide formation and closure of rings 3,7 and 8,11 is demonstrated for the D-Cys3, D-Cys7, L-Cys8, L-Cys11 nisin homologue, while interlinked rings A and B are obtained through disulfide bridges between L-Cys3 and D-Cys8 and between D-Cys7 and D-Cys11. This study offers a simple designer approach to solid phase synthesis of macrocyclic peptides and lantibiotic analogues.
Turpin
Eleanor R
ER
School of Chemistry, University of Nottingham, Nottingham, UK.
Bonev
Boyan B
BB
Hirst
Jonathan D
JD
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D003545:Cysteine / Q000737:chemistry*; D004175:Diptera / Q000737:chemistry*; D004220:Disulfides / Q000737:chemistry*; D013294:Lactococcus lactis / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D009561:Nisin / Q000737:chemistry*; D011487:Protein Conformation; D055550:Protein Stability; D013237:Stereoisomerism; D013816:Thermodynamics
D000900:Anti-Bacterial Agents; D004220:Disulfides; D009561:Nisin; D003545:Cysteine