Associate Professor of Chemistry Myriam Cotten recently published four structures in the Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB). The structures were released on January 22 after the accompanying peer-reviewed article was accepted for publication in the Journal of the American Chemical Society.
The results are the culmination of more than six years of work, funded in part by Cotten’s National Science Foundation CAREER grant. William Wieczoreck ’11 and Robert Hayden ’14 are co-authors on two of the structures. Cotten’s collaborators include Dr. Richard Pastor ’71, senior investigator in the Laboratory of Computational Biology at the National Institutes of Health and Dr. Stanley Opella at the University of California San Diego.
Antimicrobial peptides have been the focus of intense investigations in the search for new antimicrobial agents due their strong potency and low incidence of induced bacterial resistance that undermines traditional antibiotics. The new piscidin PDB entries provide the atomic-level structures of antimicrobial peptides piscidin 1 and piscidin 3 in the presence of two bacterial cell mimics.
The structures are some of the first published in the PDB to be obtained experimentally through use of solid-state Nuclear Magnetic Resonance spectroscopy. Indeed, there are more than 97,000 structures in the PDB. Only 37 (including the piscidin structures) are unique structures of peptides and proteins determined by solid-state NMR, a technique that is particularly well suited to study membrane-bound peptides under native-like conditions.
However, interpreting the solid-state NMR results collected on piscidin was challenging because NMR structures are susceptible to bias averaging due to molecular motions. Cotten and her team cross-validated the NMR structures with structures independently obtained by computational molecular dynamics simulations in Pastor's lab. The approach, which provides a rigorous benchmark for the structural elucidation of membrane-bound cationic peptides, could inspire the study of other peptides that play important roles at lipid bilayers.
Furthermore, other scientists in the field can freely access the structures and use them to test new hypotheses about the mechanisms of action of antimicrobial peptides and rationalize the design of new therapeutics with improved antimicrobial activity.
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