Antimicrobial peptides (AMPs) is an important class of biomolecules and they are known to have antimicrobial activity either by membrane disruption or action on intracellular targets. Most AMPs that have been discovered are known to disrupt bacterial membrane, but a small number of AMPs are known to translocate across the bacterial membrane and act on intracellular targets, such as bacterial DNA or ribosomes. There are various studies that propose different mechanisms of action for AMPs, but the mechanism by which they interact with bacterial membranes are still unclear. Clavanin A (ClavA, VFQFLGKIIHHVGNFVHGFSHVF-NH2), an AMP derived from the tunicate Styela clava, has a 16-fold increase in antimicrobial activity in the presence of zinc ions. The HXXXH (H17 to H21) motif near the C-terminus region can bind a zinc ion by coordination with the His residues and two water molecules. In this study, we aim to understand the role of zinc ions to the structure of ClavA and its interaction with Escherichia coli mimicking membranes through equilibrium molecular dynamics (MD) simulations. In solution studies, it was observed that binding zinc(II) stabilizes helical structures in ClavA across a range of temperatures and studies initiated in random coil states gained helicity spanning Lys7 to Val12 when zinc(II) is bound at pH 7 in the presence of E. coli mimicking membranes. Also, in most membrane systems, both termini of ClavA is found deeper within the membrane, with Phe residues in the terminal regions being buried deepest. In one instance, ClavA with zinc(II) at pH 5 presented a different mechanism of membrane penetration by having a central Phe residue (Phe15) buried deepest into the membrane. In future studies, we will look closer at the structural evolution and thermodynamics of ClavA, in the absence or presence of zinc(II), as it translocates the membrane. Overall, we are interested in giving more concrete explanations on how metal ions affect the interaction of various metal-binding AMPs that act on different types of bacterial cell membrane.

Molecular dynamics study of the role of zinc ions in Clavanin A interaction with E. coli membrane

256th National Meeting (2018)

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