Mark Santer

Quantum-classical Liouville description of multidimensional nonadiabatic molecular dynamics

The quantum-classical Liouville formulation gives a quantum-mechanical density-matrix description of the “quantum” particles of a problem (e.g., the electrons) and a classical phase-space-density description of the “classical” particles (e.g., the nuclei). In order to employ this formulation to describe multidimensional nonadiabatic processes in complex molecular systems, this work is concerned with an efficient Monte Carlo implementation of the quantum-classical Liouville equation. Although an exact stochastic realization of this equation is in principle available, in practice one has to cope with two major complications: (i) The representation of nonlocal phase-space operators in terms of local classical trajectories and (ii) the convergence of the Monte Carlo sampling which is cumbersome due to complex-valued trajectories with rapidly oscillating phases. Several strategies to cope with these problems are discussed, including various approximations to determine the momentum shift associated with a nonad...

Mixed quantum-classical Liouville molecular dynamics without momentum jump

An alternative Liouville formulation of mixed quantum-classical dynamics outlined recently [K. Ando, Chem. Phys. Lett. 360, 240 (2002)] is expanded in detail by taking an explicit account of the parametric dependence of the electronic (adiabatic) basis on the nuclear coordinates. As a consequence of the different operational order of the partial Wigner transformation for the nuclear coordinates and the calculation of the matrix elements in the adiabatic electronic basis, the present formula differs from the previously proposed one, slightly in the appearance but significantly in the treatment of nonadiabatic transitions in the trajectory implementation in that the former does not contain the “off-diagonal Hellmann–Feynman forces” representing the so-called “momentum-jump” associated with the nonadiabatic transitions. Because of this, the present formula is free from the numerical instability intrinsically coming from the momentum-jump operation at around the classical turning points of the nuclear motion....

Dynamic capillary wetting studied with dissipative particle dynamics

We present a study on dynamic capillary wetting in the framework of dissipative particle dynamics (DPD) based on a novel wall model for wetting on solid boundaries. We consider capillary impregnation of a slit pore in two situations: (i) forced (piston-driven) steady state flow and (ii) capillarity driven imbibition out of a finite reservoir. The dynamic contact angle behavior under condition (i) is consistent with the hydrodynamic theories of Cox under partial wetting conditions and Eggers for complete wetting. The flow field near the contact line shows a region of apparent slip flow which provides a natural way of avoiding a stress singularity at the triple line. The dynamics of the capillary imbibition, i.e. condition (ii), is consistently described by the Lucas–Washburn equation augmented by expressions that account for inertia and the influence of the dynamic contact angle.

Mechanical Compressibility of the Glycosylphosphatidylinositol (GPI) Anchor Backbone Governed by Independent Glycosidic Linkages

About 1% of the human proteome is anchored to the outer leaflet of cell membranes via a class of glycolipids called GPI anchors. In spite of their ubiquity, experimental information about the conformational dynamics of these glycolipids is rather limited. Here, we use a variety of computer simulation techniques to elucidate the conformational flexibility of the Man-α(1→2)-Man-α(1→6)-Man-α(1→4)-GlcNAc-α-OMe tetrasaccharide backbone 2 that is an essential and invariant part of all GPI-anchors. In addition to the complete tetrasaccharide structure, all disaccharide and trisaccharide subunits of the GPI backbone have been studied as independent moieties. The extended free energy landscape as a function of the corresponding dihedral angles has been determined for each glycosidic linkage relevant for the conformational preferences of the tetrasaccharide backbone (Man-α(1→2)-Man, Man-α(1→6)Man and Man-α(1→4)-GlcNAc). We compared the free energy landscapes obtained for the same glycosidic linkage within different oligosaccharides. This comparison reveals that the conformational properties of a linkage are primarily determined by its two connecting carbohydrate moieties, just as in the corresponding disaccharide. Furthermore, we can show that the torsions of the different glycosidic linkages within the GPI tetrasaccharide can be considered as statistically independent degrees of freedom. Using this insight, we are able to map the atomistic description to an effective, reduced model and study the response of the tetrasaccharide 2 to external forces. Even though the backbone assumes essentially a single, extended conformation in the absence of mechanical stress, it can be easily bent by forces of physiological magnitude.

Subgel Phase Structure in Monolayers of Glycosylphosphatidylinositol Glycolipids

Glycosylphosphatidylinositols (GPIs) are complex glycolipids that are commonly found in eukaryotic cells as a posttranslational modification of proteins or as free GPIs displayed on the cell surface. Although their main function is to anchor the attached protein (AP) to the cell membrane, the conserved nature of the complex pseudopentasaccharide core of GPIs (Figure 1A) suggests biological roles beyond simple physical anchoring. The GPI-APs and free GPIs show non-Brownian density fluctuations on cell surfaces, and associate with membrane microdomains, known as lipid rafts. While protein–protein interactions may contribute to the observed clustering of GPI-APs on the cell membranes, such interactions cannot be responsible for clustering of free GPIs and their association with lipid rafts. It is, therefore, conceivable that the interactions between GPI molecules and their interactions with other membrane associated species play a role in the heterogeneous distribution of GPIs in cell membranes. Some proteins that do not form clusters in the cytosol do so on the cell surface when expressed as a GPI-AP construct. Clustering of the free GPIs has also been observed on the cell surface of some parasitic protozoa. GPIs and GPI-APs are involved in a variety of biological processes, such as signal transduction, protein sorting and transport, intermembrane transfers, parasitic infections, and pathophysiology of prion diseases. Insights into the behavior of GPIs and GPI-APs in cell membranes could contribute to the understanding of the roles GPIs play in these processes. Monolayers formed with GPI-APs have been investigated, but the limited scope did not provide fundamental insights into the behavior of GPIs in cellular membranes. We aim to elucidate the structural characteristics and conformational behavior of GPIs in well-defined membrane models. Herein, we report the unprecedented ordering in two-dimensional monolayers of GlcNa1!6myoIno-1-phosphodistearylglycerol fragment of GPIs (1; Figure 1 A) observed by grazing-incidence X-ray diffraction (GIXD). Synthetic GPI mimic 1 represents a minimal fragment that might adequately emulate GPI behavior. While 1 lacks the trimannose portion present in all known GPIs, the glucosaminephosphoinositol moiety features both the amino and phosphate groups largely seen as major determinants of the behavior of the charged head groups. Compound 1 was studied in 2D films confined at the air/ liquid interface that are easy-to-handle model systems of one membrane leaflet (Figure 1A). The reduced dimensionality of the system is advantageous to better understand the role of different interactions for structure formation. To gain first insights into the molecular interactions and the possible phase transitions of compound 1 in monolayers, surface pressure/ molecular area isotherms were recorded on different subphases (Figure 1B). The water subphase was used in the presence and absence of Ca ions to test for differences that Figure 1. A) Conserved GPI structure and the structure of GlcNa1! 6myoIno-1-phosphodistearoylglycerol fragment 1. B) Surface pressure/ molecular area (p/A) isotherms on the surface of water (c), PBS (10 mm, pH 7.4, 150 mm NaCl; a), and pH 2 solution (0.01m HCl; b). C) GIXD patterns of monolayers of 1 on PBS at 20 8C (2 mN m 1 c, 30 mN m 1 a).

Photoswitchable precision glycooligomers and their lectin binding

Summary The synthesis of photoswitchable glycooligomers is presented by applying solid-phase polymer synthesis and functional building blocks. The obtained glycoligands are monodisperse and present azobenzene moieties as well as sugar ligands at defined positions within the oligomeric backbone and side chains, respectively. We show that the combination of molecular precision together with the photoswitchable properties of the azobenzene unit allows for the photosensitive control of glycoligand binding to protein receptors. These stimuli-sensitive glycoligands promote the understanding of multivalent binding and will be further developed as novel biosensors.

Manipulation of small particles at solid liquid interface: light driven diffusioosmosis

The strong adhesion of sub-micron sized particles to surfaces is a nuisance, both for removing contaminating colloids from surfaces and for conscious manipulation of particles to create and test novel micro/nano-scale assemblies. The obvious idea of using detergents to ease these processes suffers from a lack of control: the action of any conventional surface-modifying agent is immediate and global. With photosensitive azobenzene containing surfactants we overcome these limitations. Such photo-soaps contain optical switches (azobenzene molecules), which upon illumination with light of appropriate wavelength undergo reversible trans-cis photo-isomerization resulting in a subsequent change of the physico-chemical molecular properties. In this work we show that when a spatial gradient in the composition of trans- and cis- isomers is created near a solid-liquid interface, a substantial hydrodynamic flow can be initiated, the spatial extent of which can be set, e.g., by the shape of a laser spot. We propose the concept of light induced diffusioosmosis driving the flow, which can remove, gather or pattern a particle assembly at a solid-liquid interface. In other words, in addition to providing a soap we implement selectivity: particles are mobilized and moved at the time of illumination, and only across the illuminated area.

Conformational Diversity of O-Antigen Polysaccharides of the Gram-Negative Bacterium Shigella flexneri Serotype Y

O-Antigen polysaccharides constitute the outer protective layer of most Gram-negative bacteria, important for the bacteriums survival and adaption within its host. Although important for many functions, the three-dimensional structure of the dense polysaccharide coat remains to be elucidated. In this study, we present a systematic numerical investigation of O-antigen polysaccharide chains of Shigella flexneri serotype Y composed of one up to four tetrasaccharide repeat units. To bridge the gap between atomistic and coarse-grained levels of description, we employ a genuine multiscale modeling approach. It reveals that even for a few repeat units polymer-like flexibility emerges, which is furthermore complemented by extreme, hairpin-like conformations. These can facilitate the formation of metastable compact states, but this conclusion depends sensitively on the force field used to model the carbohydrates. Thus, our computational analysis represents an essential prerequisite for developing reliable coarse-grained models that may help visualizing changes in O-antigen coat morphology upon variations in chain length distribution or chemical composition of the polysaccharide characterizing a certain serotype.

Photosensitive Peptidomimetic for Light-Controlled, Reversible DNA Compaction

Light-induced DNA compaction as part of nonviral gene delivery was investigated intensively in the past years, although the bridging between the artificial light switchable compacting agents and biocompatible light insensitive compacting agents was not achieved until now. In this paper, we report on light-induced compaction and decompaction of DNA molecules in the presence of a new type of agent, a multivalent cationic peptidomimetic molecule containing a photosensitive Azo-group as a branch (Azo-PM). Azo-PM is synthesized using a solid-phase procedure during which an azobenzene unit is attached as a side chain to an oligo(amidoamine) backbone. We show that within a certain range of concentrations and under illumination with light of appropriate wavelengths, these cationic molecules induce reversible DNA compaction/decompaction by photoisomerization of the incorporated azobenzene unit between a hydrophobic trans- and a hydrophilic cis-conformation, as characterized by dynamic light scattering and AFM measurements. In contrast to other molecular species used for invasive DNA compaction, such as widely used azobenzene containing cationic surfactant (Azo-TAB, C4-Azo-OCX-TMAB), the presented peptidomimetic agent appears to lead to different complexation/compaction mechanisms. An investigation of Azo-PM in close proximity to a DNA segment by means of a molecular dynamics simulation sustains a picture in which Azo-PM acts as a multivalent counterion, with its rather large cationic oligo(amidoamine) backbone dominating the interaction with the double helix, fine-tuned or assisted by the presence and isomerization state of the Azo-moiety. However, due to its peptidomimetic backbone, Azo-PM should be far less toxic than photosensitive surfactants and might represent a starting point for a conscious design of photoswitchable, biocompatible vectors for gene delivery.

Structure binding relationship of human surfactant protein D and various lipopolysaccharide inner core structures

As a major player of the innate immune system, surfactant protein D (SP-D) recognizes and promotes elimination of various pathogens such as Gram-negative bacteria. SP-D binds to l-glycero-d-manno-heptose (Hep), a constituent of the partially conserved lipopolysaccharide (LPS) inner core of many Gram-negative bacteria. Binding and affinity of trimeric human SP-D to Hep in distinct LPS inner core glycans differing in linkages and adjacent residues was elucidated using glycan array and surface plasmon resonance measurements that were compared to in silico interaction studies. The combination of in vitro assays using defined glycans and molecular docking and dynamic simulation approaches provides insights into the interaction of trimeric SP-D with those glycan ligands. Trimeric SP-D wildtype recognized larger LPS inner core oligosaccharides with slightly enhanced affinity than smaller compounds suggesting the involvement of stabilizing secondary interactions. A trimeric human SP-D mutant D324N+D325N+R343K resembling rat SP-D bound to various LPS inner core structures in a similar pattern as observed for the wildtype but with higher affinity. The selective mutation of SP-D promotes targeting of LPS inner core oligosaccharides on Gram-negative bacteria to develop novel therapeutic agents.