We conducted over 150 ns of simulation of a protegrin-1 octamer pore in a lipid bilayer composed of palmitoyloleoyl-phosphatidylethanolamine (POPE) and palmitoyloleoyl-phosphatidylglycerol (POPG) lipids mimicking the inner membrane of a bacterial cell. The simulations improve on a model of a pore proposed from recent NMR experiments and provide a coherent understanding of the molecular mechanism of antimicrobial activity. Although lipids tilt somewhat toward the peptides, the simulated protegrin-1 pore more closely follows the barrel-stave model than the toroidal-pore model. The movement of ions is investigated through the pore. The pore selectively allows negatively charged chloride ions to pass through at an average rate of one ion every two nanoseconds. Only two events are observed of sodium ions crossing through the pore. The potential of mean force is calculated for the water and both ion types. It is determined that the chloride ions move through the pore with ease, similarly to the water molecules with the exception of a zone of restricted movement midway through the pore. In bacteria, ions moving through the pore will compromise the integrity of the transmembrane potential. Without the transmembrane potential as a countermeasure, water will readily flow inside the higher osmolality cytoplasm. We determine that the diffusivity of water through a single PG-1 pore is sufficient to cause fast cell death by osmotic lysis.

In this work, the naturally occurring beta-hairpin antimicrobial peptide protegrin-1 (PG-1) is studied by molecular dynamics simulation in all-atom sodium dodecylsulfate and dodecylphosphocholine micelles. These simulations provide a high-resolution picture of the interactions between the peptide and simple models of bacterial and mammalian membranes. Both micelles show significant disruption, as is expected for a peptide that is both active against bacteria and toxic to host cells. There is, however, clear differentiation between the behavior in SDS versus DPC, which suggests different mechanisms of interaction for PG-1 with mammalian and bacterial membranes. Specifically, the equilibrium orientation of the peptide relative to SDS is a mirror image of its position relative to DPC. In both systems, the arginine residues of PG-1 strongly interact with the head groups of the micelles. In DPC, the peptide prefers a location closer to the core of the micelle with Phe12, Val14, and Val16 imbedded in the core and the other side of the hairpin, which includes Leu5 and Tyr7, located closer to the surface of the micelle. In SDS, the peptide prefers a location at the micelle-water interface. The peptide position is reversed, with Leu5 and Cys6 imbedded furthest in the micelle core and Phe12, Val14, and Val16 on the surface of the micelle. We discuss the implications of these results with respect to activity and toxicity.

Simulations of antimicrobial peptides in membrane mimics can provide the high resolution, atomistic picture that is necessary to decipher which sequence and structure components are responsible for activity and toxicity. With such detailed insight, engineering new sequences that are active but non-toxic can, in principle, be rationalized. Armed with supercomputers and accurate force fields for biomolecular interactions, we can now investigate phenomena that span hundreds of nanoseconds. Although the phenomena involved in antimicrobial activity, (i.e., diffusion of peptides, interaction with lipid layers, secondary structure attainment, possible surface aggregation, possible formation of pores, and destruction of the lipid layer integrity) collectively span time scales still prohibitively long for classical mechanics simulations, it is now feasible to investigate the initial approach of single peptides and their interaction with membrane mimics. In this article, we discuss the promise and the challenges of widely used models and detail our recent work on peptide-micelle simulations as an attractive alternative to peptide-bilayer simulations. We detail our results with two large structural classes of peptides, helical and beta-sheet and demonstrate how simulations can assist in engineering of novel antimicrobials with therapeutic potential.

Purpose-The purpose of this paper is to report on how library and information science (LIS) as a field operationalizes the concept of organizational sustainability for managing digital resources, projects and infrastructures such as digital libraries and repositories over time. It introduces a nine dimensional framework for organizational sustainability in the digital cultural heritage community. Design/methodology/approach-Content analysis of publications from three LIS databases (2000-2015). Findings-Comparing the articles to the nine dimension framework shows that most LIS articles discuss technology, financial or management dimensions. Fewer articles describe disaster planning, assessment or policy dimensions. Research limitations/implications-Three LIS databases might not include all relevant journals, conferences, white papers and other materials. The data set also did not include books; library management textbooks might include useful material on organizational sustainability. Claims about the prevalence of themes are subject to methodological limits of content analysis. Practical implications-Organizations that steward digital collections need to be clear about what they mean when they are referring to organizational sustainability so that they can make appropriate decisions for future-proofing their collections. The analysis would also suggest for a greater need to consider the full range of dimensions of organizational sustainability. Originality/value-By introducing a new nine dimensional framework of organizational sustainability the authors hope to promote more and better conversations within the LIS community about organizational sustainability. The authors hope these conversations will lead to productive action and improvements in the arrangements of people and work necessary to keep digital projects and services going over time, given ongoing challenges.

BackgroundWe applied a combined experimental and computational approach to ascertain how peptides interact with host and microbial membrane surrogates, in order to validate simulation methodology we hope will enable the development of insights applicable to the design of novel antimicrobial peptides. We studied the interactions of two truncated versions of the potent, but cytotoxic, antimicrobial octadecapeptide protegrin-1, PC-72 [LCYCRRRFCVC] and PC-73 [CYCRRRFCVC].ResultsWe used a combination of FTIR, fluorescence spectroscopy and molecular dynamics simulations to examine the peptides' interactions with sodium dodecylsulfate (SDS) and dodecylphosphocholine (DPC) micelles. The relative amounts of secondary structure determined by FTIR agreed with those from the simulations. Fluorescence spectroscopy, deuterium exchange experiments and the simulations all indicate that neither peptide embeds itself deeply into the micelle core. Although molecular simulations placed both peptides at the micelle-water interface, further examination revealed differences in how certain residues interacted with the micelle core.ConclusionWe demonstrate here the accuracy of molecular dynamics simulations methods through comparison with experiments, and have used the simulation results to enhance the understanding of how these two peptides interact with the two types of micelles. We find agreement between simulation and experimental results in the final structure of the peptides and in the peptides final conformation with respect to the micelle. Looking in depth at the peptide interactions, we find differences in the interactions between the two peptides from the simulation data; Leu-1 on PC-72 interacts strongly with the SDS micelle, though the interaction is not persistent – the residue withdraws and inserts into the micelle throughout the simulation.