Carol K. Hall

North Carolina State University, Raleigh, North Carolina, United States

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Publications (185)569.98 Total impact

  • Steven W Benner, Vijay T John, Carol K Hall
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    ABSTRACT: Hydrophobically-modified chitosan (HMC) is being considered as a possible oil dispersant additive to reduce the volume of dispersant required in oil spill remediation. We present the results of discontinuous molecular dynamics (DMD) simulations intended to determine how the HMC architecture affects its ability to prevent oil aggregation. The HMCs have a comb copolymer architecture with hydrophobic side chains (modification chains) of various lengths (5 - 15 spheres) to represent alkane chains that are attached to the chitosan backbone. We calculated the oil's solvent accessible surface area (SASA), aggregate size distribution, and aggregate asymmetry at various values of the HMC modification chain length, modification density, and concentration to determine HMC efficacy. HMCs with long modification chains result in larger oil SASA than HMCs with short modification chains. For long modification chains there is no increase in oil SASA with increasing modification density above a saturation value. The size distribution of the oil aggregates depends on the modification chain length; systems with long modification chains lead to large aspherical aggregates while systems with short modification chains lead to small tightly packed aggregates. A parametric analysis reveals that the most important factor in determining the ability of HMCs to prevent oil aggregation is the interaction between the HMC's modification chains and the oil molecules, even when using short modification chains. We conclude that HMCs with long modification chains are likely to be more effective at preventing oil aggregation than HMCs with short modification chains, and that long modification chains impede spherical oil droplet formation.
    The Journal of Physical Chemistry B 05/2015; DOI:10.1021/acs.jpcb.5b01092 · 3.38 Impact Factor
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    ABSTRACT: Based on Brownian Dynamics computer simulations in two dimensions we investigate aggregation scenarios of colloidal particles with directional interactions induced by multiple external fields. To this end we propose a model which allows continuous change in the particle interactions from point-dipole-like to patchy-like (with four patches). We show that, as a result of this change, the non-equilibrium aggregation occurring at low densities and temperatures transforms from conventional diffusion-limited cluster aggregation (DLCA) to slippery DLCA involving rotating bonds; this is accompanied by a pronounced change of the underlying lattice structure of the aggregates from square-like to hexagonal ordering. Increasing the temperature we find a transformation to a fluid phase, consistent with results of a simple mean-field density functional theory.
  • Mookyung Cheon, Carol K Hall, Iksoo Chang
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    ABSTRACT: Discovering the mechanisms by which proteins aggregate into fibrils is an essential first step in understanding the molecular level processes underlying neurodegenerative diseases such as Alzheimer's and Parkinson's. The goal of this work is to provide insights into the structural changes that characterize the kinetic pathways by which amyloid-β peptides convert from monomers to oligomers to fibrils. By applying discontinuous molecular dynamics simulations to PRIME20, a force field designed to capture the chemical and physical aspects of protein aggregation, we have been able to trace out the entire aggregation process for a system containing 8 Aβ17-42 peptides. We uncovered two fibrillization mechanisms that govern the structural conversion of Aβ17-42 peptides from disordered oligomers into protofilaments. The first mechanism is monomeric conversion templated by a U-shape oligomeric nucleus into U-shape protofilament. The second mechanism involves a long-lived and on-pathway metastable oligomer with S-shape chains, having a C-terminal turn, en route to the final U-shape protofilament. Oligomers with this C-terminal turn have been regarded in recent experiments as a major contributing element to cell toxicity in Alzheimer's disease. The internal structures of the U-shape protofilaments from our PRIME20/DMD simulation agree well with those from solid state NMR experiments. The approach presented here offers a simple molecular-level framework to describe protein aggregation in general and to visualize the kinetic evolution of a putative toxic element in Alzheimer's disease in particular.
    PLoS Computational Biology 05/2015; 11(5):e1004258. DOI:10.1371/journal.pcbi.1004258 · 4.83 Impact Factor
  • Ravish Malik, Jan Genzer, Carol K Hall
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    ABSTRACT: We describe the utilization of protein-like copolymers (PLCs) as encapsulating agents for small molecule solutes. We perform Monte Carlo simulations on systems containing PLCs and model solute molecules in order to understand how PLCs assemble in solution and what system conditions promote solute encapsulation. Specifically, we explore how the chemical composition of the PLCs, and the range and strength of molecular interactions between hydrophobic segments on the PLC and solute molecules affect the solute encapsulation efficiency. The composition profiles of the hydrophobic and hydrophilic segments, the solute, and implicit solvent (or voids) within the PLC globule are evaluated to gain complete understanding of the behavior in the PLC/solute system. We find that a single-chain PLC encapsulates solute successfully by collapsing the macromolecule to a well-defined globular conformation when the hydrophobic/solute interaction is at least as strong as the interaction strength among hydrophobic segments and the interaction among solute molecules is at most as strong as the hydrophobic/solute interaction strength. Our results can be used by experimentalists as a framework for optimizing unimolecular PLC solute encapsulation and can be extended potentially to applications like "drug" delivery via PLCs.
    Langmuir 03/2015; 31(11). DOI:10.1021/acs.langmuir.5b00032 · 4.38 Impact Factor
  • Xingqing Xiao, Paul F. Agris, Carol K. Hall
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    ABSTRACT: A search algorithm combining Monte Carlo, self-consistent mean field, and concerted rotation techniques was developed to discover peptide sequences that are reasonable HIV drug candidates due to their exceptional binding to human tRNAUUULys3, the primer of HIV replication. The search algorithm allows for iteration between sequence mutations and conformation changes during sequence evolution. Searches conducted for different classes of peptides identified several potential peptide candidates. Analysis of the energy revealed that the asparagine and cysteine at residues 11 and 12 play important roles in “recognizing” tRNALys3 via van der Waals interactions, contributing to binding specificity. Arginines preferentially attract the phosphate linkage via charge-charge interaction, contributing to binding affinity. Evaluation of the RNA/peptide complex’s structure revealed that adding conformation changes to the search algorithm yields peptides with better binding affinity and specificity to tRNALys3 than a previous mutation-only algorithm.
    Journal of Chemical Theory and Computation 02/2015; DOI:10.1021/ct5008247 · 5.31 Impact Factor
  • Carol K Hall
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    ABSTRACT: We extend LIME, an intermediate resolution, implicit solvent model for phospholipids previously used in discontinuous molecular dynamics simulations of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) bilayer formation at 325K, to the description of the geometry and energetics of 1,2-distearoyl-sn-glycero-3-phospho-L-serine (DSPS) and 1,2-dihenarachidoyl-sn-glycero-3-phosphocholine (21PC) and mixtures thereof at both neutral and low pH at 310K. A multi-scale modeling approach is used to calculate the LIME parameters from atomistic simulation data on a mixed DPPC/DSPS system at different pH values. In the model, 17 coarse-grained sites represent DSPS and 18 coarse-grained sites represent 21PC. Each of these coarse-grained sites is classified as 1 of 9 types. LIME/DMD simulations of equimolar bilayers show the following: (1) 21PC/DSPS bilayers with and without surface area restrictions separate faster at a low pH than at a neutral pH, (2) 21PC/DSPS systems separate at approximately the same rate whether or not they are not subjected to surface area restrictions, and (3) bilayers with a molar ratio of 9:1 (21PC:DSPS) phase separate to form heterogeneous domains faster at low pH than at a neutral pH. Our results are consistent with experimental findings of Sofou and co-workers that more doxorubicin is released from 21PC/DSPS liposomes at low pH than at neutral pH, presumably because greater phase separation is achieved at low pH than at neutral pH. To our knowledge these are the first molecular-level simulations of the phase separation in mixed lipid bilayers induced by a change in pH.
    Langmuir 12/2014; DOI:10.1021/la504082x · 4.38 Impact Factor
  • ven Benner, Carol K. Hall, Vijay T. John
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    ABSTRACT: Oil spills have caused major environmental incidents over the past 50 years, and similar occurrences are likely to happen in the future. Dispersants are commonly used to clean up oil spills, however they show mild to moderate toxicity to aquatic life. There is currently a need for oil dispersant additives that are biocompatible and effective at stabilizing oil droplets in water, thereby reducing the amount of dispersant required. We are using discontinuous molecular dynamics (DMD) simulations to design a biocompatible oil dispersant additive based on hydrophobically-modified chitosan (HMC). DMD is a fast alternative to traditional molecular dynamics, that allows simulations of larger systems over longer time scales than traditional molecular dynamics Our simulations are being used to supplement experiments by Dr. Vijay John and coworkers at Tulane University who have shown that HMCs are able to prevent oil aggregation. We model HMCs as comb copolymers with a hydrophilic chitosan backbone and hydrophobic modification chains and oil molecules as short linear chains. Two simulation scenarios are considered: a bulk oil scenario (implicit water), and an interfacial oil scenario (explicit water modeled as single spheres). Bulk oil simulations begin with a random initial configuration of oil and HMCs throughout the simulation box while interfacial simulations begin with a pre-formed oil droplet and a pre-formed water/air interface. The length of the chitosan backbone (50 – 300 spheres), length of the modification chains (5-15 spheres), and the modification density (0 – 20%) are varied to determine their role in stabilizing oil in both scenarios. Preliminary results show that increasing modification chain length and modification density leads to increased oil surface area in bulk simulations, indicating that the HMCs prevent oil aggregation. HMCs with short modification chains stabilize oil by forming a chitosan backbone network and anchoring oil droplets to the chitosan network, while HMCs with long modification chains penetrate deeply into the oil droplets and deform the shape of the droplets. However, there appears to be a saturation concentration of modification spheres above which increasing modification chain length does not improve oil dispersion. Preliminary results also show that as oil droplets are exposed to an air/water interface, they spread on the water surface. HMCs applied to the air/water interface prevent the spreading of oil droplets and promote the formation of an oil gel on the water surface. The ability of HMCs to prevent oil spreading at an air/water interface has significant application in chemical herding, where a special surfactant is applied to the perimeter of an oil slick to “herd” the oil towards the center of the slick allowing in-situ burning. HMCs can be used to stabilize the already herded oil slick allowing a longer time window for the in-situ burning. Our results will be compared to experiments by John and coworkers.
    14 AIChE Annual Meeting; 11/2014
  • 14 AIChE Annual Meeting; 11/2014
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    ABSTRACT: Colloids with anisotropic charge distributions hold promise for creating a number of useful new materials including optic materials with novel symmetries, electrical materials for information storage, and dampers for controlling vibrations in structures. Because experimental characterization of the many possible types of multipolar colloidal particles that could form is difficult, the search for novel colloidal materials can be enhanced and guided by simulations of colloidal system assembly. Using a simplified potential, we have simulated a system of dipolar rods with various aspect ratios using discontinuous molecular dynamics (DMD). Each dipolar rod was modeled as several overlapping spheres held in a rod shape to represent excluded volume and two smaller, embedded spheres to represent the charges that make up the extended dipole. We have discovered the existence of fluid, string-fluid, and “gel” phases at low volume fractions and nematic phases at high volume fractions. We have also developed a more realistic discontinuous Yukawa-like potential that allows us to examine colloidal rods that exhibit either head-to-tail or side-by-side configurations depending on the internal charge separation. The percolation probability, maximum cluster size and heat capacity have been monitored to evaluate the aggregation properties of these particles as a function of temperature. The mean squared displacement (MSD) has also been calculated to follow the dynamics. Preliminary results show that at low temperatures the rods assemble to form strands when the head-to-tail configuration is preferred and into rectangular aggregates when the side-by-side configuration is preferred. While the above simulations were all performed in 3d, we have also performed 2d simulations of the same system of dipolar rods corresponding more closely to experiments in which the colloidal particles are confined between plates. Finally, we have also looked into the effect that adding an external electric field has on the system and have observed an increased propensity for chaining in the system.
    14 AIChE Annual Meeting; 11/2014
  • Carol K. Hall, Mookyung Cheon, Iksoo Chang
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    ABSTRACT: Protein aggregation is associated with serious and eventually-fatal neurodegenerative diseases including Alzheimer’s and Parkinson’s. While atomic resolution molecular dynamics simulations have been useful in this regard, they are limited to examination of either oligomer formation by a small number of peptides or analysis of the stability of a moderate number of peptides placed in trial or known experimental structures. We describe large scale intermediate-resolution molecular dynamics simulations of the spontaneous formation of fibrils by systems containing large numbers (48-96) of peptides including A-beta (16-22),( 17-42), (1-40) and (1-42) . We trace out the aggregation process from an initial configuration of random coils to oligomers and then to proto-filaments with cross-β structures and demonstrate how kinetics dictates the structural details of the fully formed fibril. Particular noteworthy are our simulation results for a system of 8 Aβ17-42 peptides. Protofilaments containing the U-shape β-sheet structures seen in solid state NMR experiments by the Tycko group are realized in simulations starting from random chains, the first time that this has been observed computationally. We observe two different conformational conversion from disordered oligomers to ordered protofilament: (1) one-by-one monomeric conversion to a fibrillar structure, and (2) very slow conversion of a meta-stable oligomer with “S”-shaped chains to a fibrillar structure. The relatively long life of the metastable S-shaped oligomers compared to that of the U-shaped oligomers that we see in our simulations suggests that S-shaped oligomers are likely to be toxic, as has been suggested in recent experiments by the Smith group. Movies of the aggregation process on a molecular level will be shown.
    14 AIChE Annual Meeting; 11/2014
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    ABSTRACT: Therapeutic RNA delivery technology is a promising method for treating chronic or acute diseases, which works by enabling cell-based therapeutics to directly reprogram gene expression in host cells. This RNA delivery strategy, however, faces several major barriers to clinical treatment. One of these barriers is the difficulty of identifying appropriate RNA binding peptides to “load” cargo (therapeutic) RNA. In this work, our focus is on the complex formed by the λ N36 peptide and boxB RNA, because a specific recognition of boxB RNA by λ N36 peptide and a high affinity of the complex (Kd = 1.3 nM) has been found. Additionally, our collaborator Joshua Leonard of Northwestern University is using this complex as a model system to engineer exosomes with the ultimate goal of therapeutic RNA delivery. We have developed a computational search algorithm to design RNA binding peptides that mimic the λ N36 peptide’s ability to bind selectively to the boxB RNA (cargo RNA). Our search algorithm involves the concerted rotation move (CONROT) and Monte Carlo (MC) techniques. The CONROT technique is employed to move the peptide during the search for conformation candidates. When changing the peptide sequence, a new energy minimization strategy is performed to optimize the configuration of the side chains on the trial amino acids. We calculate the score for these new attempted sequences and conformations, and then employ the MC technique to accept or reject the attempted sequences and conformations based on the Metropolis sampling method. Through performing the search algorithm, we generated a library of good RNA binding peptides that are capable of recognizing and binding the boxB RNA with a range of affinities. The best RNA binding peptide sequence was identified among these designed peptides; it exhibits a higher binding affinity to boxB RNA (score: -144.32 kcal/mol) than λ N36 peptide (score: -138.81 kcal/mol). A further structural and energetic analysis reveals that the best peptide has 6 identical residues at the same sites as the λ N36 peptide, and its binding specificity to boxB RNA becomes strengthened as the inter-chain van der Waals energy decreases (becomes more negative).
    14 AIChE Annual Meeting; 11/2014
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    ABSTRACT: To examine the effect of crowding on protein aggregation, discontinuous molecular dynamics (DMD) simulations combined with an intermediate resolution protein model, PRIME20, were applied to a peptide/crowder system. The systems contained 192 Aβ(16-22) peptides and crowders of diameters 5Å, 20Å, and 40Å, represented here by simple hard spheres, at crowder volume fractions of 0.00, 0.10, and 0.20. Results show that both crowder volume fraction and crowder diameter have a large impact on fibril and oligomer formation. The addition of crowders to a system of peptides increases the rate of oligomer formation, shifting from a slow ordered formation of oligomers in the absence of crowders, similar to nucleated polymerization, to a fast collapse of peptides and subsequent rearrangement characteristic of nucleated conformational conversion with a high maximum in the number of peptides in oligomers as total crowder surface area increases. The rate of conversion from oligomers to fibrils also increases with increasing total crowder surface area, giving rise to an increased rate of fibril growth. In all cases, larger volume fractions and smaller crowders provide the greatest aggregation enhancement effects. We also show that the size of the crowders influences the formation of specific oligomer sizes. In our simulations the 40Å crowders enhance the number of dimers relative to the numbers of trimers, hexamers, pentamers, and hexamers, while the 5Å crowders enhance the number of hexamers relative to the numbers of dimers, trimers, tetramers, and pentamers. These results are in qualitative agreement with previous experimental and theoretical work.
    The Journal of Physical Chemistry B 10/2014; DOI:10.1021/jp508970q · 3.38 Impact Factor
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    ABSTRACT: Elastin-like polypeptides (ELPs) with the repeat sequence of VPGVG are widely used as a model system for investigation of lower critical solution temperature (LCST) transition behavior. In this paper, the effect of temperature on the structure, dynamics and association of (VPGVG)18 in aqueous solution is investigated using atomistic molecular dynamics simulations. Our simulations show that as the temperature increases the ELP backbones undergo gradual conformational changes, which are attributed to the formation of more ordered secondary structures such as β-strands. In addition, increasing temperature changes the hydrophobicity of the ELP by exposure of hydrophobic valine-side chains to the solvent and hiding of proline residues. Based on our simulations, we conclude that the transition behavior of (VPGVG)18 can be attributed to a combination of thermal disruption of the water network that surrounds the polypeptide, reduction of solvent accessible surface area of the polypeptide, and increase in its hydrophobicity. Simulations of the association of two (VPGVG)18 molecules demonstrated that the observed gradual changes in the structural properties of the single polypeptide chain are enough to cause the aggregation of polypeptides above the LCST. These results lead us to propose that the LCST phase behavior of poly(VPGVG) is a collective phenomenon that originates from the correlated gradual changes in single polypeptide structure and the abrupt change in properties of hydration water around the peptide and is a result of a competition between peptide-peptide and peptide-water interactions. This is a computational study of an important intrinsically disordered peptide system that provides an atomic-level description of structural features and interactions that are relevant in the LCST phase behavior.
    Biomacromolecules 08/2014; 15(10). DOI:10.1021/bm500658w · 5.79 Impact Factor
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    ABSTRACT: The goal of this work is to understand how the sequence of a protein affects the likelihood that it will form an amyloid fibril and the kinetics along the fibrillization pathway. The focus is on very short fragments of amyloid proteins since these play a role in the fibrillization of the parent protein and can form fibrils themselves. Discontinuous molecular dynamics simulations using the PRIME20 force field were performed of the aggregation of 48-peptide systems containing SNQNNF (PrP (170-175), SSTSAA (RNaseA(15-20), MVGGVV (Aβ(35-40)), GGVVIA (Aβ(37-42) and MVGGVVIA (Aβ(35-42)). In our simulations SNQQNF, SSTTSAA and MVGGVV form large numbers of fibrillar structures spontaneously (as in experiment). GGVVIA forms β-sheets that do not stack into fibrils (unlike experiment). The combination sequence MVGGVVIA forms less fibrils than MVGGVV, hindered by the presence of the hydrophobic residues at the C- terminal. Analysis of the simulation kinetics and energetics reveals why MVGGVV forms fibrils and GGVVIA does not, and why adding I and A to MVGGVVIA reduces fibrillization and enhances amorphous aggregation into oligomeric structures. The latter helps explain why Aβ(1-42) assembles into more complex oligomers than Aβ(1-40), a consequence of which is that it is more strongly associated with Alzheimer's disease. © Proteins 2014;. © 2014 Wiley Periodicals, Inc.
    Proteins Structure Function and Bioinformatics 07/2014; 82(7). DOI:10.1002/prot.24515 · 2.92 Impact Factor
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    ABSTRACT: In the present work we perform Monte Carlo simulations in the isothermal-isobaric ensemble to study defect topologies formed in a cholesteric liquid crystal due to the presence of a spherical colloidal particle. Topological defects arise because of the competition between anchoring at the colloidal surface and the local director. We consider homogeneous colloids with either local homeotropic or planar anchoring to validate our model by comparison with earlier lattice Boltzmann studies. Furthermore, we perform simulations of a colloid in a twisted nematic cell and discuss the difference between induced and intrinsic chirality on the formation of topological defects. We present a simple geometrical argument capable of describing the complex three-dimensional topology of disclination lines evolving near the surface of the colloid. The presence of a Janus colloid in a cholesteric host fluid reveals a rich variety of defect structures. Using the Frank free energy we analyze these defects quantitatively indicating a preferred orientation of the Janus colloid relative to the cholesteric helix.
    Soft Matter 06/2014; 10(30). DOI:10.1039/c4sm00959b · 4.15 Impact Factor
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    ABSTRACT: How nanoparticles interact with biomembranes is central for understanding their bioactivity. Biomembranes wrap around nanoparticles if the adhesive interaction between the nanoparticles and membranes is sufficiently strong to compensate for the cost of membrane bending. In this article, we review recent results from theory and simulations that provide new insights on the interplay of bending and adhesion energies during the wrapping of nanoparticles by membranes. These results indicate that the interplay of bending and adhesion during wrapping is strongly affected by the interaction range of the particle-membrane adhesion potential, by the shape of the nanoparticles, and by shape changes of membrane vesicles during wrapping. The interaction range of the particle-membrane adhesion potential is crucial both for the wrapping process of single nanoparticles and the cooperative wrapping of nanoparticles by membrane tubules.
    Advances in Colloid and Interface Science 03/2014; 208. DOI:10.1016/j.cis.2014.02.012 · 8.64 Impact Factor
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    ABSTRACT: Human tRNA(Lys3)UUU is the primer for replication HIV. The HIV-1 nucleocapsid protein, NCp7, facilitates htRNA(Lys3)UUU recruitment from the host cell by binding to and remodeling the tRNA structure. Human tRNA(Lys3)UUU is post-transcriptionally modified, but until recently the importance of those modifications in tRNA recognition by NCp7 was unknown. Modifications such as the 5-methoxycarbonylmethyl-2-thiouridine at anticodon wobble position-34 and 2-methylthio-N6-threonylcarbamoyladenosine, adjacent to the anticodon at position-37, are important to the recognition of htRNA(Lys3)UUU by NCp7. Several short peptides selected from phage display libraries were found to also preferentially recognize these modifications. Evolutionary algorithms (Monte Carlo and self-consistent mean field) and Assisted Model Building with Energy Refinement were used to optimize the peptide sequence in silico while fluorescence assays were developed and conducted to verify the in silico results and elucidate a 15-amino acid signature sequence (R-W-Q/N-H-X2-F-Pho-X-G/A-W-R-X2-G, where X can be most amino acids and Pho is hydrophobic) that recognized the tRNA's fully modified anticodon stem and loop domain, hASL(Lys3)UUU. Peptides of this sequence specifically recognized and bound modified tRNALys3 with an affinity 10-fold higher than the starting sequence. Thus, this approach provides an effective means of predicting sequences of RNA binding peptides that have better binding properties. Such peptides can be used in cell and molecular biology, as well as biochemistry to explore RNA binding proteins, and to inhibit those protein functions.
    Biochemistry 01/2014; 53(7). DOI:10.1021/bi401174h · 3.19 Impact Factor
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    ABSTRACT: Dynamic rheology in combination with Fourier transform infrared spectroscopy (FTIR) is used to examine the gelation kinetics, mechanism, and gel point of novel thiol−acrylate systems containing varying concentrations of an in situ catalyst. Gelation, as evidenced from the gel time determined using the Winter− Chambon criterion, is found to occur more quickly with increasing catalyst concentration up until a critical catalyst concentration of 22 mol %, whereupon the gel time lengthens. Such a minimum in gel time may be attributed to changes in the number of available reaction sites and percentage conversion required for gelation. Chemical conversions at the gel point measured for representative samples are consistent with theoretical values calculated using Flory−Stockmayer's statistical approach, confirming our hypothesis. Relaxation exponents of 0.97 and fractal dimensions of 1.3 are calculated for all samples, consistent with coarse-grained discontinuous molecular dynamics (DMD) simulations. The elevated value of n may be due to the low molecular weight prepolymer. The relaxation exponent and fractal dimensions are invariable over all systems studied, suggesting the cross-linking mechanism remains unaffected by changes in catalyst concentration, allowing the gel time to be tailored by simply modulating the catalyst concentration. ■ INTRODUCTION Polymerization via thiol−ene chemistry, the addition of a thiol group over a carbon−carbon double bond, has experienced a renewed interest in recent years. Materials synthesized using this approach are easily processed due to a solvent-free, rapid synthesis that can occur at room temperature and ambient pressure, yielding materials with high conversion 1 and uniform cross-link densities. 2,3 As a result of these benefits, thiol−ene polymerization schemes are being used in various applications such as functionalization of nanoparticles, 4−7 surface mod-ification, 8,9 and fabrication of biomaterials. 10
    Macromolecules 01/2014; 47(2). DOI:10.1021/ma402157f · 5.93 Impact Factor
  • Xingqing Xiao, Paul F Agris, Carol K Hall
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    ABSTRACT: The mechanism by which proteins recognize and bind the post-transcriptional modifications of RNAs is unknown, yet these interactions play important functions in biology. Atomistic molecular dynamics simulations were performed to examine the folding of the model peptide chain -RVTHHAFLGAHRTVG- and the complex formed by the folded peptide with the native anticodon stem and loop of the human tRNA(Lys3) (hASL(Lys3)) in order to explore the binding mechanism. By analyzing and comparing two folded conformations of this peptide obtained from the folding simulation, we found that the van der Waals (VDW) energy is necessary for the thermal stability of the peptide, and the charge-charge (ELE + EGB) energy is crucial for determining the three-dimensional folded structure of the peptide backbone. Subsequently, two conformations of the peptide were employed to investigate their binding behaviors to hASL(Lys3). The metastable folded peptide was found to bind to hASL(Lys3) much easier than the stable folded peptide in the binding simulations. An energetic analysis reveals that the VDW energy favors the binding, whereas the ELE + EGB energies disfavor the binding. Arginines on the peptide preferentially attract the phosphate backbone via the inter-chain ELE + EGB interaction, significantly contributing to the binding affinity. The hydrophobic phenylalanine interacts with the anticodon loop of hASL(Lys3) via the inter-chain VDW interaction, significantly contributing to the binding specificity.
    Journal of biomolecular Structure & Dynamics 01/2014; 33(1). DOI:10.1080/07391102.2013.869660 · 2.98 Impact Factor

Publication Stats

4k Citations
569.98 Total Impact Points

Institutions

  • 1157–2015
    • North Carolina State University
      • Department of Chemical and Biomolecular Engineering
      Raleigh, North Carolina, United States
  • 2013
    • Technische Universität Berlin
      Berlín, Berlin, Germany
  • 2011
    • Pusan National University
      • Department of Physics
      Pusan, Busan, South Korea
  • 2003
    • University of California, San Francisco
      San Francisco, California, United States
  • 2002
    • Duke Raleigh Hospital
      Raleigh, North Carolina, United States
  • 1980–1989
    • Princeton University
      • Department of Chemical and Biological Engineering
      Princeton, NJ, United States