Rational combinatorial design of pore-forming -sheet peptides

Rational combinatorial design of pore-forming -sheet peptides

Exogenous polypeptides that self-assemble on biological membranes into pores are abundant and structurally diverse, functioning as transporters, toxins, ion channels, and antibiotics. A means for designing novel pore-forming sequences would unlock new opportunities for the development and engineering of protein function in membranes. Toward this goal, we designed a 9,604member rational combinat...

Beta-sheet pore-forming peptides selected from a rational combinatorial library: mechanism of pore formation in lipid vesicles and activity in biological membranes.

In a previous report we described the selection of potent, beta-sheet pore-forming peptides from a combinatorial library designed to mimic membrane-spanning beta-hairpins (Rausch, J. M., Marks, J. R., and Wimley, W. C. (2005) Proc. Natl. Acad. Sci. U.S.A. 102, 10511-10515). Here, we characterize their mechanism of action and compare the structure-function relationships in lipid vesicles to thei...

Phase diagram of alpha-helical and beta-sheet forming peptides.

The intrinsic property of proteins to form structural motifs such as alpha helices and beta sheets leads to a complex phase behavior in which proteins can assemble into various types of aggregates including crystals, liquidlike phases of unfolded or natively folded proteins, and amyloid fibrils. Here we use a coarse-grained protein model that enables us to perform Monte Carlo simulations for de...

A high-throughput screen for identifying transmembrane pore-forming peptides.

We have developed a visual microwell plate assay for rapid, high-throughput screening for membrane-disrupting molecules such as de novo designed pore formers, antibiotic peptides, bacterial toxins, and lipases. The detectability is based on the strong fluorescence emission of the lanthanide metal terbium(III) (Tb(3+)) when it interacts with the aromatic chelator dipicolinic acid (DPA). While Tb...

Prediction and Rational Design of Antimicrobial Peptides