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Biomedical subjects

Ronald G Larson

Publications and source records attributed to Ronald G Larson.

At least 19 recordsLinked to original sources

Methods of stretching DNA molecules using flow fields.

Using fluorescence microscopy, we compare the degree of adsorption and stretching of DNA onto surfaces achieved by published stretching methods that use fluid flow: molecular combing, spin-stretching, and air-blowing. Molecular combing uses a receding meniscus to stretch out and deposit the DNA onto a hydrophobic surface. In spin-stretching, we find that the effect of radial hydrodynamic flow created by the centrifugal force of the rotating disk is minimal and that the DNA is stretched out on a hydrophobic substrate by the moving meniscus. In air-blowing, a jet of gas pushes liquid across a substrate, depositing stretched DNA molecules along the way. In our study, DNA molecules either combed or spin-stretched onto hydrophobic surfaces stretch to a greater degree than those that are air-blown; fewer are deposited at pH 8.0 than at lower pH, apparently because at pH 8.0 DNA adhesion occurs primarily only at the DNA extremities and so avoids trapped regions of incompletely stretched DNA, with the side effect that more molecules avoid adhesion altogether. We find by high-speed video microscopy that there is complex droplet deformation and motion during air-blowing, which complicates the deposition and stretching process, leading to radial alignment. Our results are a first step toward understanding and optimizing the various proposed methods of DNA stretching and anchoring onto surfaces, which is important in studying their interactions with proteins.

Adsorption↗

Molecular dynamics simulations of PAMAM dendrimer-induced pore formation in DPPC bilayers with a coarse-grained model.

We have performed 0.5-micros-long molecular dynamics (MD) simulations of 0%, 50%, and 100% acetylated third- (G3) and fifth-generation (G5) polyamidoamine (PAMAM) dendrimers in dipalmitoylphosphatidylcholine (DPPC) bilayers with explicit water using the coarse-grained (CG) model developed by Marrink et al. (J.Phys. Chem. B 2004, 108, 750-760), but with long-range electrostatic interactions included. Radii of gyration of the CG G5 dendrimers are 1.99-2.32 nm, close to those measured in the experiments by Prosa et al. (J. Polym. Sci. 1997, 35, 2913-2924) and atomistic simulations by Lee et al. (J. Phys. Chem. B 2006, 110, 4014-4019). Starting with the dendrimer initially positioned near the bilayer, we find that positively charged un-acetylated G3 and 50%-acetylated and un-acetylated G5 dendrimers insert themselves into the bilayer, and only un-acetylated G5 dendrimer induces hole formation at 310 K, but not at 277 K, which agrees qualitatively with experimental observations of Hong et al. (Bioconj. Chem. 2004, 15, 774-782) and Mecke et al. (Langmuir 2005, 21, 10348-10354). At higher salt concentration (approximately 500 mM NaCl), un-acetylated G5 dendrimer does not insert into the bilayer. The results suggest that with inclusion of long-range electrostatic interactions into coarse-grained models, realistic MD simulation of membrane-disrupting effects of nanoparticles at the microsecond time scale is now possible.

1,2-Dipalmitoylphosphatidylcholine↗

Cation and anion transport through hydrophilic pores in lipid bilayers.

To understand the origin of transmembrane potentials, formation of transient pores, and the movement of anions and cations across lipid membranes, we have performed systematic atomistic molecular dynamics simulations of palmitoyl-oleoyl-phosphatidylcholine (POPC) lipids. A double bilayer setup was employed and different transmembrane potentials were generated by varying the anion (Cl-) and cation (Na+) concentrations in the two water compartments. A transmembrane potential of approximately 350 mV was thereby generated per bilayer for a unit charge imbalance. For transmembrane potential differences of up to approximately 1.4 V, the bilayers were stable, over the time scale of the simulations (10-50 ns). At larger imposed potential differences, one of the two bilayers breaks down through formation of a water pore, leading to both anion and cation translocations through the pore. The anions typically have a short residence time inside the pore, while the cations show a wider range of residence times depending on whether they bind to a lipid molecule or not. Over the time scale of the simulations, we do not observe the discharge of the entire potential difference, nor do we observe pore closing, although we observe that the size of the pore decreases as more ions translocate. We also observed a rare lipid flip-flop, in which a lipid molecule translocated from one bilayer leaflet to the opposite leaflet, assisted by the water pore.

Anions↗

The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4.

The molecular basis of nephronophthisis, the most frequent genetic cause of renal failure in children and young adults, and its association with retinal degeneration and cerebellar vermis aplasia in Joubert syndrome are poorly understood. Using positional cloning, we here identify mutations in the gene CEP290 as causing nephronophthisis. It encodes a protein with several domains also present in CENPF, a protein involved in chromosome segregation. CEP290 (also known as NPHP6) interacts with and modulates the activity of ATF4, a transcription factor implicated in cAMP-dependent renal cyst formation. NPHP6 is found at centrosomes and in the nucleus of renal epithelial cells in a cell cycle-dependent manner and in connecting cilia of photoreceptors. Abrogation of its function in zebrafish recapitulates the renal, retinal and cerebellar phenotypes of Joubert syndrome. Our findings help establish the link between centrosome function, tissue architecture and transcriptional control in the pathogenesis of cystic kidney disease, retinal degeneration, and central nervous system development.

Activating Transcription Factor 4↗

Marangoni effect reverses coffee-ring depositions.

We show here both experimentally and theoretically that the formation of "coffee-ring" deposits observed at the edge of drying water droplets requires not only a pinned contact line but also suppression of Marangoni flow. For simple organic fluids, deposition actually occurs preferentially at the center of the droplet, due to a recirculatory flow driven by surface-tension gradients produced by the latent heat of evaporation. The manipulation of this Marangoni flow in a drying droplet should allow one in principle to control and redirect evaporation-driven deposition and assembly of colloids and other materials.

Letter↗

Effect of salt on the interactions of antimicrobial peptides with zwitterionic lipid bilayers.

The effect of salt on the binding of the antimicrobial peptide magainin to POPC lipid bilayers is studied by 40-50 ns molecular dynamics simulations of a POPC bilayer in the presence of different concentrations of Na+ and Cl- ions, corresponding to effective concentrations of 0, 100, 150, 200, 250 and 300 millimolar NaCl, with and without a single molecule of antimicrobial peptide magainin. Simulations without magainin showed that increasing salt concentration leads to the decrease in the area per lipid, a decrease in the head group tilt of the lipids, as well as increased order of lipid tails, in agreement with other recent simulations. Simulations with magainin show that peptide binding to the lipids is stronger at lower concentrations of salt. The peptides disorder the lipids in their immediate vicinity, but this effect is diminished as the salt concentration increases. Our studies indicate that while 50 ns simulations give information on peptide hydrogen bonding and lipid tail ordering that is insensitive to the initial peptide orientation, this run time is not sufficient to equilibrate the peptide position and orientation within the bilayer.

Amino Acid Sequence↗

Molecular dynamics studies of the size, shape, and internal structure of 0% and 90% acetylated fifth-generation polyamidoamine dendrimers in water and methanol.

We have performed molecular dynamics simulations of 0% and 90% acetylated fifth-generation (G5) polyamidoamine (PAMAM) dendrimers in water and methanol and obtained radii of gyration of 2.51-2.57 and 2.11-2.33 nm, respectively, similar to those measured experimentally in methanol by Prosa et al. (J. Polym. Sci. 1997, 35, 2913-2924) and in water by Choi et al. (Nano Lett. 2004, 4, 391-397). Calculation of the moments of inertia and the relative shape anisotropy show that both 0% and 90% acetylated G5 are modestly ellipsoidal. The distribution of branch points relative to the center of the dendrimer and penetration of solvent show that the core and surface of the dendrimer are more exposed to water than is the region between the core and the surface due to the interactions between monomers, including hydrogen bonds that rapidly break and re-form as solvent molecules compete for hydrogen-bonding sites on the monomers. The water and methanol solvents seem to produce similar numbers of hydrogen bond interactions between monomers.

Acetylation↗

Brownian dynamics simulations with stiff finitely extensible nonlinear elastic-Fraenkel springs as approximations to rods in bead-rod models.

A very stiff finitely extensible nonlinear elastic (FENE)-Fraenkel spring is proposed to replace the rigid rod in the bead-rod model. This allows the adoption of a fast predictor-corrector method so that large time steps can be taken in Brownian dynamics (BD) simulations without over- or understretching the stiff springs. In contrast to the simple bead-rod model, BD simulations with beads and FENE-Fraenkel (FF) springs yield a random-walk configuration at equilibrium. We compare the simulation results of the free-draining bead-FF-spring model with those for the bead-rod model in relaxation, start-up of uniaxial extensional, and simple shear flows, and find that both methods generate nearly identical results. The computational cost per time step for a free-draining BD simulation with the proposed bead-FF-spring model is about twice as high as the traditional bead-rod model with the midpoint algorithm of Liu [J. Chem. Phys. 90, 5826 (1989)]. Nevertheless, computations with the bead-FF-spring model are as efficient as those with the bead-rod model in extensional flow because the former allows larger time steps. Moreover, the Brownian contribution to the stress for the bead-FF-spring model is isotropic and therefore simplifies the calculation of the polymer stresses. In addition, hydrodynamic interaction can more easily be incorporated into the bead-FF-spring model than into the bead-rod model since the metric force arising from the non-Cartesian coordinates used in bead-rod simulations is absent from bead-spring simulations. Finally, with our newly developed bead-FF-spring model, existing computer codes for the bead-spring models can trivially be converted to ones for effective bead-rod simulations merely by replacing the usual FENE or Cohen spring law with a FENE-Fraenkel law, and this convertibility provides a very convenient way to perform multiscale BD simulations.

Algorithms↗

Molecular dynamics simulations of model trans-membrane peptides in lipid bilayers: a systematic investigation of hydrophobic mismatch.

Hydrophobic mismatch, which is the difference between the hydrophobic length of trans-membrane segments of a protein and the hydrophobic width of the surrounding lipid bilayer, is known to play a role in membrane protein function. We have performed molecular dynamics simulations of trans-membrane KALP peptides (sequence: GKK(LA)nLKKA) in phospholipid bilayers to investigate hydrophobic mismatch alleviation mechanisms. By varying systematically the length of the peptide (KALP15, KALP19, KALP23, KALP27, and KALP31) and the lipid hydrophobic length (DLPC, DMPC, and DPPC), a wide range of mismatch conditions were studied. Simulations of durations of 50-200 ns show that under positive mismatch, the system alleviates the mismatch predominantly by tilting the peptide and to a smaller extent by increased lipid ordering in the immediate vicinity of the peptide. Under negative mismatch, alleviation takes place by a combination of local bilayer bending and the snorkeling of the lysine residues of the peptide. Simulations performed at a higher peptide/lipid molar ratio (1:25) reveal slower dynamics of both the peptide and lipid relative to those at a lower peptide/lipid ratio (1:128). The lysine residues have favorable interactions with specific oxygen atoms of the phospholipid headgroups, indicating the preferred localization of these residues at the lipid/water interface.

Algorithms↗

Protein-assisted stretching and immobilization of DNA molecules in a microchannel.

We demonstrate a novel technique we call "protein-assisted DNA immobilization" (PADI), to immobilize and stretch, but not overstretch, DNA molecules inside a micro/nanochannel with limited surface interactions while maintaining continuous hydration at physiological pH. The biological activity of the immobilized DNA molecules is confirmed by digesting the DNA with restriction enzymes in the microchannel. Single-molecule transcription, which has stringent requirements on the immobilized DNA with respect to surface interactions and stretched lengths, is also successfully demonstrated on DNA molecules immobilized by PADI. In addition to arraying DNA molecules for study of DNA-protein interactions, the immobilization method could be used to construct DNA-templated nanoelectronic devices.

DNA↗

Molecular dynamics simulations of the anchoring and tilting of the lung-surfactant peptide SP-B1-25 in palmitic acid monolayers.

We have performed molecular dynamics simulations of multiple copies of the lung-surfactant peptide SP-B1-25 in a palmitic acid (PA) monolayer. SP-B1-25 is a shorter version of lung-surfactant protein B, an important component of lung surfactant. Up to 30 ns simulations of 20 wt % SP-B1-25 in the PA monolayers were performed with different surface areas of PA, extents of PA ionization, and various initial configurations of the peptides. Starting with initial peptide orientation perpendicular to the monolayer, the predicted final tilt angles average 54 degrees approximately 62 degrees with respect to the monolayer normal, similar to those measured experimentally by Lee et al. (Biophysical Journal. 2001. Synchrotron x-ray study of lung surfactant-specific protein SP-B in lipid monolayers. 81:572-585). In their final conformations, hydrogen-bond analysis and amino acid mutation studies show that the peptides are anchored by hydrogen bond interactions between the cationic residues Arg-12 and Arg-17 and the hydrogen bond acceptors of the ionized PA headgroup, and the tilt angle is affected by the interactions of Tyr-7 and Gln-19 with the PA headgroup. Our work indicates that the factors controlling orientation of small peptides in lipid layers can now be uncovered through molecular dynamics simulations.

Adsorption↗

Analysis of the effects of Marangoni stresses on the microflow in an evaporating sessile droplet.

We study the effects of Marangoni stresses on the flow in an evaporating sessile droplet, by extending a lubrication analysis and a finite element solution of the flow field in a drying droplet, developed earlier. The temperature distribution within the droplet is obtained from a solution of Laplace's equation, where quasi-steadiness and neglect of convection terms in the heat equation can be justified for small, slowly evaporating droplets. The evaporation flux and temperature profiles along the droplet surface are approximated by simple analytical forms and used as boundary conditions to obtain an axisymmetric analytical flow field from the lubrication theory for relatively flat droplets. A finite element algorithm is also developed to solve simultaneously the vapor concentration, and the thermal and flow fields in the droplet, which shows that the lubrication solution with the Marangoni stress is accurate for contact angles as high as 40 degrees. From our analysis, we find that surfactant contamination, at a surface concentration as small as 300 molecules/microm(2), can almost entirely suppress the Marangoni flow in the evaporating droplet.

Journal Article↗

Analysis of the microfluid flow in an evaporating sessile droplet.

The axisymmetric time-dependent flow field in an evaporating sessile droplet whose contact line is pinned is studied numerically and using an analytical lubrication theory with a zero-shear-stress boundary condition on the free surface of the droplet at low capillary and Reynolds numbers. A finite element algorithm is developed to solve simultaneously the vapor concentration and flow field in the droplet under conditions of slow evaporation. The finite element solution confirms the accuracy of the lubrication solution, especially when terms of higher order in the droplet flatness ratio (the ratio of droplet height to radius, h/R) are included in the lubrication theory to account more accurately for the singular flow near the contact line.

Biopolymers↗

Chain retraction potential in a fixed entanglement network.

When a chain, tethered at one end, is immersed in a fixed entanglement network, the mobile tip of the chain encounters an entropic potential barrier that penalizes deep fluctuations needed to bring the tip close to the tethering point. Using the tube model, Doi and Kuzuu [J. Polym. Sci., Polym. Lett. Ed. 18, 775 (1980)] estimated that this potential, which is crucial to describe the rheology of branched polymers in fixed networks and melts, has a quadratic form with a prefactor nu = 1.5. Later calculations based on regular lattices indicated that the potential is nonquadratic, and its steepness depends on the lattice coordination number. In this Letter, we analyze the primitive paths obtained using the bond-fluctuation model for chains with up to 12.5 entanglements. Our simulations confirm a quadratic form for the potential with a prefactor close to the Doi-Kuzuu value, nu approximately 1.5.

Journal Article↗

Atomic force microscopic study of aggregation of RecA-DNA nucleoprotein filaments into left-handed supercoiled bundles.

RecA and its complexes with double-stranded DNA (dsDNA) and single-stranded DNA (ssDNA) are responsible for homologous recombination and DNA repair. In this study, we have observed, by atomic force microscopy (AFM), two-filament left-handed superhelices of RecA-dsDNA filaments that further interwind into four- or six-filament bundles, in addition to previously reported left-handed bundles of three or six filaments. Also revealed are four-filament bundles formed by further interwinding of two intrafilament superhelices of individual filaments. Pitches of superhelices of RecA-DNA filaments are similar to each other regardless the number of component filaments, and those formed on Phix174 RFII dsDNA and pNEB206A dsDNA are measured as 339.3 +/- 6.2 nm (690 counts of pitch/2) and 321.6 +/- 11.7 nm (101 counts of pitch/2), respectively, consistent with earlier measurements made by electron microscopy with a much smaller sample size. The study of these structures provides insight into the self-interactions of RecA and RecA-like proteins, which are present in all living cells, and into the general phenomenon of bundling, which is relevant to both biological and nonbiological filaments.

Binding Sites↗

Molecular dynamics study of the lung surfactant peptide SP-B1-25 with DPPC monolayers: insights into interactions and peptide position and orientation.

We have performed molecular dynamics simulations of the interactions of the peptide SP-B(1-25), which is a truncated version of the full pulmonary surfactant protein SP-B, with dipalmitoylphosphatidylcholine monolayers, which are the major lipid components of lung surfactant. Simulations of durations of 10-20 ns show that persistent hydrogen bonds form between the donor atoms of the protein and the acceptors of the lipid headgroup and that these bonds determine the position, orientation, and secondary structure of the peptide in the membrane environment. From an ensemble of initial conditions, the most probable equilibrium orientation of the alpha-helix of the peptide is predicted to be parallel to the interface, matching recent experimental results on model lipid mixtures. Simulations of a few mutated analogs of SP-B(1-25) also suggest that the charged amino acids are important in determining the position of the peptide in the interface. The first eight amino acids of the peptide, also known as the insertion sequence, are found to be essential in reducing the fluctuations and anchoring the peptide in the lipid/water interface.

1,2-Dipalmitoylphosphatidylcholine↗

Performance of an analytical, dual infrared-beam, stored-product insect monitoring system.

A system is described for automated monitoring of pest insects in stored grain. It provides quantitative data indicative of the species of detected insects and is self-calibrating to maintain reliable operation over time across adverse environmental and biological conditions. The system uses electronic grain probes, each with a dual infrared-beam sensor head providing orthogonal views of falling insects. Sensor analog signals are analyzed by an embedded microprocessor, and extracted waveform parameters are transmitted back to a central computer. Filtering algorithms recognize and eliminate false detections due to extraneous (nonfalling) insect activities and provide an indication of species based on body size. Laboratory test data provide species identification templates and an analysis of Montana field test data acquired in aerated and nonaerated bins demonstrates the effectiveness of the filtering algorithms. The described system technology has been licensed by OPIsystems, Inc., Calgary, Alberta, Canada, and is commercially available as Insector.

Animals↗

One-step preparation of highly monodisperse micron-size particles in organic solvents.

In this communication, we report the first simple and fast one-step method for synthesizing highly monodisperse micron-size PMMA particles in organic media through dispersion polymerization in the presence of PHSA (a polyhydroxyl-stearic-acid graft PMMA copolymer) as a stabilizer. There are two significant advantages of our method over earlier methods. First, by optimizing the composition of a solvent mixture of hexane and dodecane, we were able to increase the concentration of monomer up to 50-56% and obtain unusually large (up to 10 mum in diameter) PMMA particles. Second, by strictly controlling the nucleation time, we were able to make PMMA particles with a low polydispersity of around 1%, much lower than has ever before been achieved for such large particles. We also report an unusual apparent metastable state in the nucleation stage.

Journal Article↗