Compaction and clustering of a heterogeneous polymer by biomolecular crowding.

Inspired by bacterial chromosome organization, we study the compaction and clustering of a heterogeneous ring polymer in a crowded medium using molecular dynamics simulations. The polymer consists of several large monomers interspersed along the backbone and small intervening monomers. In a crowded medium, the entropy of crowding particles or crowders favors the collapse of chain molecules, such as chromosomes.

Modeling the compaction of bacterial chromosomes by biomolecular crowding and the cross-linking protein H-NS.

Cells orchestrate the action of various molecules toward organizing their chromosomes. Using a coarse-grained computational model, we study the compaction of bacterial chromosomes by the cross-linking protein H-NS and cellular crowders. In this work, H-NS, modeled as a mobile "binder," can bind to a chromosome-like polymer with a characteristic binding energy.

Modeling selectivity of antimicrobial peptides: how it depends on the presence of host cells and cell density.

Antimicrobial peptides (AMPs), naturally-occurring peptide antibiotics, are known to attack bacteria selectively over the host cells. The emergence of drug-resistant bacteria has spurred much effort in utilizing optimized (more selective) AMPs as new peptide antibiotics. Cell selectivity of these peptides depends on various factors or parameters such as their binding affinity for cell membranes, peptide trapping in cells, peptide coverages on cell membranes required for membrane rupture, and cell densities.

Interplay between nematic and cholesteric interactions in self-consistent field theory.

Chirality is a design feature of a number of biomolecules (e.g., collagen).

Self-consistent field theory of chiral nematic worm-like chains.

Many macromolecules of biological and technological interest are both chiral and semi-flexible. DNA and collagen are good examples. Such molecules often form chiral nematic (or cholesteric) phases, as is well-documented in collagen and chitin.

Modeling Cell Selectivity of Antimicrobial Peptides: How Is the Selectivity Influenced by Intracellular Peptide Uptake and Cell Density.

Antimicrobial peptides (AMPs) are known to attack bacteria selectively over their host cells. Many attempts have been made to use them as a template for designing peptide antibiotics for fighting drug-resistant bacteria. A central concept in this endeavor is "peptide selectivity," which measures the "quality" of peptides.

Collapse transition of a heterogeneous polymer in a crowded medium.

Long chain molecules can be entropically compacted in a crowded medium. We study the compaction transition of a heterogeneous polymer with ring topology by crowding effects in a free or confined space. For this, we use molecular dynamics simulations in which the effects of crowders are taken into account through effective interactions between chain segments.

Modeling the Protective Role of Bacterial Lipopolysaccharides against Membrane-Rupturing Peptides.

Lipopolysaccharide (LPS) is a key surface component of Gram-negative bacteria, populating the outer layer of their outer membrane. A number of experimental studies highlight its protective role against harmful molecules such as antibiotics and antimicrobial peptides (AMPs). In this work, we present a theoretical model for describing the interaction between LPS and cationic antimicrobial peptides, which combines the following two key features.

Characteristic time for the end monomers of a spherically confined polymer to find a nano-pore.

Translocation of a polymer through a nano-pore is relevant in a variety of contexts such as passage of RNAs through a nuclear pore and transportation of proteins across a membrane. An essential step in polymer translocation is for the end monomers to search the pore. This process requires a characteristic time, referred to as the "attempt time" in this work.

Nematic ordering of worm-like polymers near an interface.

The phase behavior of semi-flexible polymers is integral to various contexts, from materials science to biophysics, many of which utilize or require specific confinement geometries as well as the orientational behavior of the polymers. Inspired by collagen assembly, we study the orientational ordering of semi-flexible polymers, modeled as Maier-Saupe worm-like chains, using self-consistent field theory. We first examine the bulk behavior of these polymers, locating the isotropic-nematic transition and delineating the limit of stability of the isotropic and nematic phases.

Toward building a physical model for membrane selectivity of antimicrobial peptides: making a quantitative sense of the selectivity.

Antimicrobial peptides (AMPs) are naturally-occurring peptide antibiotics. AMPs are typically cationic and utilize their electrostatic interactions with the bacterial membrane to selectively attack bacteria. The way they work has inspired a vigorous search for optimized peptides for fighting resistant bacteria.

Confinement induces helical organization of chromosome-like polymers.

Helical organization is commonly observed for a variety of biopolymers. Here we study the helical organization of two types of biopolymers, i.e.

Heterogeneous absorption of antimicrobial peptide LL37 in cells enhances population survivability.

Antimicrobial peptides (AMPs) are broad spectrum antibiotics that selectively target bacteria. Here we investigate the activity of human AMP LL37 against by integrating quantitative, population and single-cell level experiments with theoretical modeling. We observe an unexpected, rapid absorption and retention of a large number of LL37 peptides by cells upon the inhibition of their growth, which increases population survivability.

Opposing effects of cationic antimicrobial peptides and divalent cations on bacterial lipopolysaccharides.

The permeability of the bacterial outer membrane, enclosing Gram-negative bacteria, depends on the interactions of the outer, lipopolysaccharide (LPS) layer, with surrounding ions and molecules. We present a coarse-grained model for describing how cationic amphiphilic molecules (e.g.

A ring-polymer model shows how macromolecular crowding controls chromosome-arm organization in Escherichia coli.

Macromolecular crowding influences various cellular processes such as macromolecular association and transcription, and is a key determinant of chromosome organization in bacteria. The entropy of crowders favors compaction of long chain molecules such as chromosomes. To what extent is the circular bacterial chromosome, often viewed as consisting of "two arms", organized entropically by crowding? Using computer simulations, we examine how a ring polymer is organized in a crowded and cylindrically-confined space, as a coarse-grained bacterial chromosome.

How are molecular crowding and the spatial organization of a biopolymer interrelated.

In a crowded cellular interior, dissolved biomolecules or crowders exert excluded volume effects on other biomolecules, which in turn control various processes including protein aggregation and chromosome organization. As a result of these effects, a long chain molecule can be phase-separated into a condensed state, redistributing the surrounding crowders. Using computer simulations and a theoretical approach, we study the interrelationship between molecular crowding and chain organization.

Effects of molecular crowding and confinement on the spatial organization of a biopolymer.

A chain molecule can be entropically collapsed in a crowded medium in a free or confined space. Here, we present a unified view of how molecular crowding collapses a flexible polymer in three distinct spaces: free, cylindrical, and (two-dimensional) slit-like. Despite their seeming disparities, a few general features characterize all these cases, even though the ϕ-dependence of chain compaction differs between the two cases: a > a and a < a, where ϕ is the volume fraction of crowders, a is the monomer size, and a is the crowder size.

Chromosome-like organization of an asymmetrical ring polymer confined in a cylindrical space.

To what extent does a confined polymer show chromosome-like organization? Using molecular dynamics simulations, we study a model Escherichia coli (E. coli) chromosome: an asymmetrical ring polymer, formed by small monomers on one side and big monomers on the other confined in a concentric-shell or simple cylinder with closed ends. The ring polymer is organized in the way observed for the E.

How Cell Concentrations Are Implicated in Cell Selectivity of Antimicrobial Peptides.

Antimicrobial peptides (AMPs) are known to selectively bind to and kill microbes over host cells. Contrary to a conventional view, there is now evidence that AMP's cell selectivity varies with cell densities and is not uniquely determined. Using a coarse-grained model, we study how the cell selectivity of membrane-lytic AMPs, defined as the ratio between their minimum hemolytic (MHC) and minimum inhibitory concentrations (MIC), depends on cell densities or on the way it is measured.

Polymers under confinement: single polymers, how they interact, and as model chromosomes.

How confinement or a physical constraint modifies polymer chains is not only a classical problem in polymer physics but also relevant in a variety of contexts such as single-molecule manipulations, nanofabrication in narrow pores, and modelling of chromosome organization. Here, we review recent progress in our understanding of polymers in a confined (and crowded) space. To this end, we highlight converging views of these systems from computational, experimental, and theoretical approaches, and then clarify what remains to be clarified.

A polymer in a crowded and confined space: effects of crowder size and poly-dispersity.

DNA compaction in a bacterial cell is in part carried out by entropic (depletion) forces induced by "free" proteins or crowding particles in the cytoplasm. Indeed, recent in vitro experiments highlight these effects by showing that they alone can condense the E. coli chromosome to its in vivo size.

Activation kinetics of zipper molecular beacons.

Proteases play key roles in the regulation of normal cellular function, and thus, their deregulation leads to many disease states. Molecular beacons are promising protease-imaging probes for the detection and characterization of disease as well as for the evaluation of treatment. Inspired by this, we examined the efficiency of zipper molecular beacons (ZMBs) as imaging probes.

Surface-lattice model describes electrostatic interactions of ions and polycations with bacterial lipopolysaccharides: ion valence and polycation's excluded area.

The bacterial outer membrane (OM) is compositionally distinct and contains polyanionic lipopolysaccharide (LPS) in the outer layer as a main component. It has long been known that the cation-binding ability of LPS is one of the key determinants of OM permeability. Here we present a two-dimensional lattice model of the outer LPS layer, in which the lattice is decorated with bound ions or polycations; while small ions can occupy single binding sites, polycations, modeled as (charged) rods, compete for binding sites through their area exclusion, a consequence of their multisite binding.

Electrostatic modification of the lipopolysaccharide layer: competing effects of divalent cations and polycationic or polyanionic molecules.

The outer membrane (OM) of Gram-negative bacteria is asymmetrical with its outer layer mainly populated with polyanionic lipopolysaccharide (LPS). Much empirical evidence shows how OM permeability can be altered electrostatically: if Mg(2+) or divalent cations are required for the integrity of the OM, antimicrobial peptides (AMPs) or ethylene-diaminetetraacetic acid (EDTA) can permeabilize it. Using a coarse-grained model of the outer LPS layer, in which the layer is viewed as forming discrete binding sites for opposite charges, we study how the LPS layer can be modified electrostatically.

Physical manipulation of the Escherichia coli chromosome reveals its soft nature.

Replicating bacterial chromosomes continuously demix from each other and segregate within a compact volume inside the cell called the nucleoid. Although many proteins involved in this process have been identified, the nature of the global forces that shape and segregate the chromosomes has remained unclear because of limited knowledge of the micromechanical properties of the chromosome. In this work, we demonstrate experimentally the fundamentally soft nature of the bacterial chromosome and the entropic forces that can compact it in a crowded intracellular environment.