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What Makes a Good Pore Former: A Study of Synthetic Melittin Derivatives.

ABSTRACT: Pore formation by membrane-active peptides, naturally encountered in innate immunity and infection, could have important medical and technological applications. Recently, the well-studied lytic peptide melittin has formed the basis for the development of combinatorial libraries from which potent pore-forming peptides have been derived, optimized to work under different conditions. We investigate three such peptides, macrolittin70, which is most active at neutral pH; pHD15, which is active only at low pH; and MelP5_Δ6, which was rationally designed to be active at low pH but formed only small pores. There are three, six, and six acidic residues in macrolittin70, pHD15, and MelP5_Δ6, respectively. We perform multi-microsecond simulations in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) of hexamers of these peptides starting from transmembrane orientations at neutral pH (all residues at standard protonation), low pH (acidic residues and His protonated), and highly acidic environments in which C-termini are also protonated. Previous simulations of the parent peptides melittin and MelP5 in 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) are repeated in POPC. We find that the most potent pore-forming peptides exhibit strong interpeptide interactions, including salt bridges, H-bonds, and polar interactions. Protonation of the C-terminus promotes helicity and pore size. The proximity of the peptides allows fewer lipid headgroups to line the pores than in previous simulations, making the pores intermediate between barrel stave and toroidal. Based on these structures and geometrical arguments, we attempt to rationalize the factors that under different conditions can increase or decrease pore stability and propose mutations that could be tested experimentally.

SUBMITTER: Sepehri A

PROVIDER: S-EPMC7175419 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:We explored traits that promote plant invasions. External factors affecting invasion success consist of various abiotic and biotic constraints. How well plants perform under those depends on multiple characteristics, such as life history traits, genetic variation patterns, competitive and dispersal abilities, phenotypic plasticity, resistance, tolerance, and possibly allelopathic interactions. Since the introduction of invasive species is often connected with humans, their geographical distribution and differentiation may not reflect adaptation. However, a lack of adaptation may be compensated for by repeated introductions via mixing genotypes from multiple populations or through novel mutations. As a case study, we used data from the Global Invasive Species Database of IUCN and attempted to reveal factors contributing to invasiveness. The most prevalent features are that the dispersal is strongly human assisted, many species are used as ornamentals, disturbed habitats are favored, and most species are perennial. Distribution features show that the worst invasive species typically have a narrower native distribution, but both groups, i.e., most serious invasive and other listed invasive species, have commonly developed a multicontinental distribution. The change in the multicontinental distribution from 6% to 63% in most serious invasive species reflects their effectiveness in global dispersal and establishment. High proportions of invasive species in both groups have mixed reproduction systems, i.e., they have the ability to propagate both sexually and asexually (57% and 50%, respectively). This provides flexibility for spreading and establishment. A lower proportion of the worst invasive species was mainly/only sexual (23%, often hermaphrodites) when compared to other invasive plants (40%). In the case of sexual reproduction, hermaphroditism combined with self-compatibility may enhance invasiveness, since selfing allows fertilization and recombination even under low population densities. Overall, the ability for asexual propagation and, in the case of sexuality, hermaphroditism, is an asset in the invasion process.

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What Makes a Good Pore Former: A Study of Synthetic Melittin Derivatives.

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