Lecture 16: Dr. Yukun Wang (Martin Ulmschneider Lab)

Experimentally guided simulations reveal the mechanism of action of antimicrobial peptides

Since their discovery over 100 years ago, thousands of pore-forming antimicrobial peptides (AMPs) have been identified, revealing great variations in size, secondary structure and sequence composition. Despite this wealth of data no common pore-forming motif has been discovered, and the molecular basis of antimicrobial activity remains poorly understood. One of the key difficulties has been the transience of pores formed by AMPs, which has proved challenging for experimental structure determination. In the absence of experimental structures a range of theoretical models have been proposed that try to rationalize how soluble AMPs, which carry multiple charged residues, can insert into hydrophobic membranes to form pores and what these pores might look like.

Spontaneous membrane insertion and intra-membrane
oligomerization of maculatin [1]

Scientists from the Johns Hopkins Institue of NanoBio technology reports[1] an experimentally guided unbiased simulation methodology that yields the mechanism of spontaneous pore assembly for the AMP maculatin at atomic resolution. Rather than a single pore, maculatin forms an ensemble of structurally diverse temporarily functional low-oligomeric pores, which mimic integral membrane protein channels in structure. These pores continuously form and dissociate in the membrane. Membrane permeabilization is dominated by hexa-, hepta- and octamers, which conduct water, ions and small dyes. Pores were shown to form by consecutive addition of individual helices to a transmembrane helix or helix bundle, in contrast to current poration models. The diversity of the pore architectures—formed by a single sequence—may be a key feature in preventing bacterial resistance and could explain why sequence–function relationships in AMPs remain elusive.

Related References:

[1] Wang, Y., Chen, C. H., Hu, D., Ulmschneider, M. B., & Ulmschneider, J. P. (2016). Spontaneous formation of structurally diverse membrane channel architectures from a single antimicrobial peptide. Nature Communications, 7.

[2] Wimley, W. C., & Hristova, K. (2011). Antimicrobial peptides: successes, challenges and unanswered questions. The Journal of membrane biology, 239(1-2), 27-34.

[3] Ulmschneider, M. B., Ulmschneider, J. P., Schiller, N., Wallace, B. A., Von Heijne, G., & White, S. H. (2014). Spontaneous transmembrane helix insertion thermodynamically mimics translocon-guided insertion. Nature communications, 5, 4863.

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Dr. Yukun Wang did his undergrad in Biology in Nanjing Agricultural University. After graduation, he did his Ph.D. in Biophysics at the Institute of Natural Sciences & School Of Life Sciences And Biotechnology, Shanghai Jiao Tong University. Currently, he is a postdoctoral fellow at the Institute for Nano-Bio-Technology in the Whiting School of Engineering at The Johns Hopkins University working with Prof. Martin Ulmschneider. Dr. Wang's research interests span from the functional mechanism of antimicrobial peptides to developing free energy calculation algorithms for rare event dynamics in the lipid-peptides systems. He enjoys computational designing of membrane-active peptides and proteins.