The Role of Binding Specificity in Limiting the Number of Realizable Self-Assembled Structures: Towards the Stabilization of a Shell

unavailable Plasticity and Polymorphism within the Amyloid Cross-Beta Motif Berryman, Josh Leeds University (UK) Amyloid fibrils are dissimilar to native-folded proteins in that a variety of stably folded forms will commonly exist for the same protein sequence. Numerical techniques are used to investigate the forces which select between these conformations (polymorphs) and to analyse the responsivity of the different polymorphs (plasticity) in the amyloidogenic protein fragment GNNQQNY. Protofibrils of two and four parallel beta-sheets, derived from the crystal structure are examined as well as invented systems composed of antiparallel beta-sheet. The antiparallel systems are found to have approximately equivalent free-energies to the parallel systems under a range of conditions and the network of adaptive, mutually balancing, interactions which permits this to occur is illustrated using simple geometric and statistical techniques. DNA repair triggered by sensors of helical dynamics Krastan B. Blagoev Los Alamos National Laboratory Nucleotide excision repair is a ubiquitous cut and patch mechanism that eliminates DNA lesions induced by multiple genotoxic agents. Unlike the recombinatorial approach of the immune system, which generates billions of immunoglobulins and T-cell receptors, the nucleotide excision repair complex uses only few generic factors to recognize an infinite range of base modifications. New data favor an unexpected strategy predicted by theoretical calculations, whereby damage recognition is initiated by the detection of abnormal oscillations in the undamaged strand opposite to DNA lesions. Another core subunit recognizes the increased susceptibility of DNA to be kinked at injured sites. Thus, early nucleotide excision repair factors avoid direct contacts with modified bases and, instead, achieve their broad molecular versatility by exploiting the altered dynamics of damaged DNA. Genetic catalysis of metabolic containers in a minimal protocell DeClue, Michael Los Alamos National Laboratory The goal of the project is to transform simple inanimate molecules into an organized system resembling living units through a bottom-up approach. In particular, the coupling of two man-made chemical processes, one mimicking metabolism and the other heredity, inside of a dividing chemical compartment is needed. Our initial strategy attempts to genetically regulate the conversion of synthetic precursors into fatty acid based lipids inducing the formation, growth and division of chemical containers or vesicles. Precursor molecules are designed to undergo photolytic conversion into protocellular building blocks via a metabolic mediated process using a nucleic acid coupled with a transition metal complex as a cofactor. Photolysis kinetics may ultimately show a rate dependency on nucleic acid sequence, providing the system a mechanism for evolutionary control. Towards this goal, we have successfully used a derivative of a nucleotide (8-oxo-guanine) that acts as an electron donor in a photoinduced electron transfer cleavage reaction providing carboxylic acid from ester precursor. The system uses a ruthenium containing photocatalyst to harvest visible light energy and shuttle an electron to ester molecules releasing decanoic acid. While the initial reaction mixture is a homogeneous aqueous solution, as the photolysis proceeds the solution becomes opalescent over time suggesting that inhomogeneous structures are forming. Indeed, after 24 h of exposure the reaction was significantly complete (>95%) and the solution contained bilayer vesicles and tubular structures as confirmed through fluorescence microscopy. Control experiments under matching conditions using a guanine-based catalyst showed only very low background reaction (<5%) after 24 h with the solution remaining homogenous without structures. Since guanine has the lowest oxidation potential of the natural bases its the most likely nucleotide to participate in an electron transfer process with [Ru(bpy)3]2+. The inability of guanine to catalyze the reaction demonstrates that the process is dependent upon the presence of a specific information molecule having the correct redox potential and is therefore base specific. This implies that certain nucleic acid sequences embedded with at least one oxoG may lead to systems with enhanced catalytic efficiencies having inheritable advantages. The design criterion for our protocell uses an operational definition of a living system in which a container, a metabolic process and an information material interact to transform resources into building blocks which assemble into a container that can grow, divide, and undergo evolution. While we still have many experimental hurdles to overcome before realizing our protocell the above results are a significant advancement towards our design. Molecular theory of lipid bilayers: Effects of alcohols and pore-forming peptides Frischknecht, Amalie Sandia National Laboratories Lipid bilayers are important inhomogeneous fluid systems that mediate the interaction of cells with their environment. We have applied a classical density functional theory (DFT) to a coarse-grained model of lipid and solvent, designed to self-assemble into a bilayer. I will present two recent results: the effects of alcohols on the mechanical properties of lipid bilayers, and the structure and free energy of pores formed in the bilayer by assemblies of model peptides. Ab initio study of exciton transfer dynamics from a core–shell semiconductor quantum dot to a porphyrin-sensitizer Kilin, Dmitri Los Alamos National Laboratory The observed resonance energy transfer in nanoassemblies of CdSe/ZnS quantum dots and pyridyl-substituted freebase porphyrin molecules [Zenkevich et al., J. Phys. Chem. B 109 (2005) 8679] is studied computationally by ab initio electronic structure and quantum dynamics approaches. The system harvests light in a broad energy range and can transfer the excitation from the dot through the porphyrin to oxygen, generating singlet oxygen for medical applications. The geometric structure, electronic energies, and transition dipole moments are derived by density functional theory and are utilized for calculating the Förster coupling between the excitons residing on the quantum dot and the porphyrin. The direction and rate of the irreversible exciton transfer is determined by the initial photoexcitation of the dot, the dot– porphyrin coupling and the interaction to the electronic subsystem with the vibrational environment. The simulated electronic structure and dynamics are in good agreement with the experimental data and provide real-time atomistic details of the energy transfer mechanism. Electronic Properties of DNA Base Molecules Adsorbed on a Metallic Surface Kilina, Svetlana Los Alamos National Laboratory The internal electronic structure of single deoxyribonucleic acid (DNA) base molecules, i.e. guanine, adenine, cytosine, and thymine, adsorbed on a metallic surface of Cu(111), is determined in detail using density functional theory (DFT) computations. In contrast to the intuitive belief that a molecule weakly interacts with a substrate and its electronic structure is only slightly perturbed, our simulations reveal strong hybridizations and interactions between molecular and metallic states. Stipulated by the symmetries of a base molecule and the Cu(111) surface, oxygen atoms of a base approach close to the substrate, breaking the parallel orientation of the $\pi$-system with respect to the surface. Such a behavior is the most pronounced for one oxygen containing bases, leading to the chemisorption of cytosine and guanine and stronger hybridization of their electronic states with metallic ones. Oxygen free adenine, on the other hand, lies nearly flat on a Cu substrate and interacts weakly with the surface through physisorption. The calculated local electron density of states spectra demonstrate the absence of pure localized molecular states for all four DNA bases, yet, show the smallest delocalization for adenine and thymine and the largest for guanine and cytosine. The observed diversity of the geometrical and electronic structures of the nucleobases on the Cu substrate provides guidelines for interpreting DNA tunneling spectra in the scanning tunneling microscopy (STM) measurements. Our results open a new prospective for understanding bio-molecule adsorbates and have an important implication for a possible differentiation of nucleotide sequences in DNA through STM. Simulation of water in nanoconfinement between self-assembled monolayers Lane, J. Matthew D. Sandia National Laboratories Abstract unavailableunavailable 3D tracking of individual quantum dots Lessard, Guillaume Los Alamos National Laboratory We describe an instrument that extends the state of the art in single-molecule tracking technology, allowing extended observations of single fluorophores and fluorescently-labeled proteins as they undergo directed and diffusive transport in three dimensions. Our instrument is based on a modified confocal microscope geometry with multiple single-photon detectors. We demonstrate 3D tracking of single quantum dots diffusing at rates comparable to those of intracellular signaling processes. Dynamics, Rectification, and Fractionalization for Colloids on Flashing Substrates Libal, Andras University of Notre Dame We show that a rich variety of dynamic phases can be realized for monoand bidisperse mixtures of interacting colloids under the influence of a symmetric flashing periodic substrate. With the addition of dc or ac drives, phase locking, jamming, and new types of ratchet effects occur. In some regimes we find that the addition of a non-ratcheting species increases the velocity of the ratcheting particles. We show that these effects occur due to the collective interactions of the colloids. Structural Model for Estane Based on Self-Consistent Field Theory Maniadis, Panagiotis Los Alamos National Laboratory We are investigating the equilibrium properties of multi-block copolymer melts using self consistent field theory (SCF). Our model block copolymer is Estane 5703, which is a multi-block with 28 repeats of alternating soft and hard segments. About one-fourth of the hard segments are present as oligomers with the remainder being monomers separated by soft segments. The SCF model has been extended to include this level of structural complexity. The mechanical properties of this material arise from the phase separation of the components and the creation of hard and soft domains. The oligomeric and monomeric hard segments have different temperature dependent separation properties which accounts for the gradual softening of the material as the temperature is raised. We use the SCF theory to study the phase separation processes and determine the contribution of the detailed structure to the elastic properties. SCF theory is also now extended to explicitly include the elastic fields (stress and strain), allowing further inspection of the structural contributions to the mechanical properties. LA-UR-06-2665, LA-UR-07-0466 Modeling aggregation of multivalent biomolecules in cellular systems. Monine, Michael Los Alamos National Laboratory Aggregation of receptors on cell surface by extracellular multivalent ligand initiates a variety of biochemical reactions at early stages of signal transduction in cells. It is a dynamic process; alterations in kinetics of receptor aggregation can result in different levels of receptor activity. This, in turn, modifies intracellular regulatory pathways that include reactions between cytoplasmic signaling molecules. For example, receptor aggregate formation is vital for proper functioning in many antigen, hormone and cytokine receptor systems that control immunological reactions [1-3]. Recent studies of signal transduction in T cells have shown that receptor aggregation can also be mediated by intracellular molecules, such as adaptor and effector proteins, which act cooperatively [2]. In last two decades, the phenomenon of receptor aggregation has been studied by many groups, both experimentally and mathematically. In experimental systems, however, an exact statistics on receptor aggregates cannot be obtained yet. Therefore, the simulations, in which dynamics of aggregates is quantified explicitly, are of great benefit to understanding the kinetics of aggregation. Aggregation phenomenon is associated with the exponential increase in the number of chemical species and distinct cross-linking interactions, therefore, dynamic simulations of such complex biomolecular systems with the help of conventional methods (such as ODEs, etc.) become intractable. To resolve the complexity of this problem, we propose a stochastic algorithm based on Gillespie method [4]. Our kinetic model is originally designed for well-mixed systems, however, in case of diffusion-limited interactions, diffusion effects can be included as corrections to the reaction rates. To validate the simulation results, we use a thermodynamic equilibrium theory that quantifies all possible configurations on the surface [5]. We apply the developed model to simulate recent experimental data obtained for various systems of multivalent interactions [2,3,6]. Using reasonable values of kinetic parameters in the developed model, we are able to reproduce quantitatively the experimental observations. We are currently working on generalization of the algorithm and incorporating it in to a rulebased software [7]. References: 1.Hlavacek et al., Biophys. J., 76, 2421 (1999). 2.Houtman et al., Nat. Struct. Mol. Biol., 13, 798 (2006). 3.Bilgicer et al., J. Am. Chem. Soc., 129, 3722 ( 2007). 4.Gillespie D.T., Ann. Rev. Phys. Chem., 58, 35 (2007); Gillespie D.T., J. Phys. Chem., 81, 2340 (1977). 5.Goldstein et al., Biophys. J., 45, 1109 (1984). 6.Posner R.G., Chemistry and Biology, Northern Arizona University, Flagstaff, AZ. Private communication. 7.Blinov et al., Bioinformatics, 20, 3289 (2004). Collective Behavior in Epithelial Sheets Murrell, Michael Massachusetts Institute of Technology The movement of epithelial sheets plays fundamental roles in the development and renewal of complex tissues, from the separation of early embryonic tissue to homeostasis in the adult intestine. Yet, considering its broad importance as an essential biological process, it has eluded a clear and quantitative interpretation in physical terms, prohibited by the lack of understanding of the basic relationship between motility, cell-cell contact, and their mediation by the physical environment. In particular, the factors that influence how physical interactions that originate at the cellular level, i.e. the balance between cell-cell and cell-matrix stability evolve to bring about stable multi-cellular behavior are completely unknown, complicated by seemingly contradictory observations. Most glaringly, the presumed translation of cells on soft media (basal lamina), and the physical role of cell division (as a motive force) in this process constitute two physical paradoxes in the movement of epithelial sheets. Thus, in this study, we use statistical methods to quantify the precise cell-cell interaction as mediated by adhesion to surfaces that are constant in adhesivity, but vary in rigidity. We further use this uncovered relationship to prove that sheet motion is not an individual effort, but collective whose degree is mediated by modes of adhesion to a substrate. How does a straight polymer relax? Obermayer, Benedict Ludwig-Maximilians-Universität Munich Although the relaxation dynamics of semiflexible polymers from an initially straight conformation has been discussed extensively in the literature, this seemingly simple problem involves nontrivial physics that is not yet completely understood. This is partly due to the ambiguous meaning of ``initially straight'', for which various realizations are conceivable. The filament could be stretched (by optical tweezers, electric fields, elongational flows, ...), but it could also be quenched, i.e., prepared in an initial low-temperature environment. In all cases, the longitudinal contraction is driven by the same purely stochastic forces, yet the resulting deterministic growth laws for pertinent observables reflect for short times fundamental differences in the underlying relaxation processes. We present a comprehensive explanation how these differences emanate from the various realizations and how they give rise to universal long-time relaxation. Further, we compare my theoretical results to recent experiments and simulations, give suggestions on how to test our predictions, and comment on the choice of proper observables. Quantum dynamics of isomerization Making a Bio-molecule qubit for a quantum computer Santamore, Deborah Los Alamos National Laboratory Abstract unavailable A unified geometric theory of mesoscopic stochastic pumps and reversible ratchets. Sinitsyn, Nikolai Los Alamos National Laboratory I will present a unifying theory of geometric effects in mesoscopic stochastic kinetics, such as the adiabatic pump and the reversible ratchet effects, as well as similar phenomena in other domains. I will show that all they follow from geometric phase contributions to the effective action in the stochastic path integral representation of the moment generating function of particle fluxes. The theory provides a universal technique for identification, prediction and calculation of pump-like phenomena in an arbitrary mesoscopic stochastic framework. The applications to a simple Michaelis-Menten reaction as well as to complicated biochemical reaction networks will be reviewed. Studies of myoglobin dynamics by dielectric relaxation spectroscopy Stroe, Izabela Los Alamos National Laboratory Proteins are dynamic molecules and their motions are intimately linked to the fluctuations of their solvent environment. In this work we studied the protein-solvent interactions by measuring the dielectric response of horse myoglobin (Mb) in glycerol/H2O mixtures over a frequency range of 40Hz-110MHz. Two relaxation processes were observed at temperatures above 220K. The high frequency process corresponds to the fluctuations of the glycerol/H2O solvent and its rates were found to increase slightly at the presence of the Mb protein. The low frequency process, slower by roughly four orders of magnitude, is relevant to Mb motions and absent for the samples without Mb. The temperature dependence of the two processes can be approximated with the same Vogel-Tammann-Fulcher temperature dependence. Preliminary analyses suggest that the Mb-related process is associated with the conformational fluctuations of the whole Mb protein. Such fluctuations require the coordinated motions of surrounding solvent molecules and are thus an example of protein slaving to the solvent fluctuations Simulation of suspensions of hydrodynamically interacting self-propelled particles Underhill, Patrick University of Wisconsin, Madison Recently large collections of swimming microorganisms have been observed producing collective motions on a scale much larger than the scale of a single organism. To better understand the cause of these motions, simulations of large populations of hydrodynamically interacting swimming particles have been performed at low Reynolds number in periodic and confined geometries. Each swimmer is modeled as a rod containing beads with a propulsion force exerted on one bead (with an equal and opposite force exerted on the fluid) and excluded volume potentials at the beads. At small concentrations, the swimmers behave analogously to a dilute gas in which the hydrodynamic interactions perturb the ballistic trajectories into diffusive motion. Simple scaling arguments can explain the swimmer behavior as well as the behavior of passive tracer particles. As the concentration increases, the multi-body hydrodynamic interactions lead to large-scale collective motion.