Dan McElheny

The Scripps Research Institute, La Jolla, California, United States

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Publications (28)136.81 Total impact

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    ABSTRACT: The interaction of redox-active Cu ions with misfolded amyloid β (Aβ) is linked to production of reactive oxygen species (ROS), which has been associated with oxidative stress and neuronal damages in Alzheimer's disease (AD). Despite intensive studies, it is still not conclusive how the interaction of Cu(+)/Cu(2+) with Aβ aggregates leads to ROS production even at the in-vitro level. In this study, we examined the interaction between Cu(+)/Cu(2+) and Aβ fibrils by solid-state NMR (SSNMR) and other spectroscopic methods. Our photometric studies confirmed the production of ~60 μM hydrogen peroxide (H2O2) from a solution of 20 μM Cu(2+) ions in complex with Aβ(1-40) in fibrils ([Cu(2+)]/[Aβ] = 0.4) within 2 hours of incubation after addition of biological ascorbate at the physiological concentration (~1 mM). Furthermore, SSNMR (1)H T1 measurements demonstrated that during ROS production, conversion of paramagnetic Cu(2+) into diamagnetic Cu(+) occurs while the reactive Cu(+) ions remain bound to the amyloid fibrils. The results also suggest that O2 is required for rapid recycling of Cu(+) bound to Aβ back to Cu(2+), which allows for continuous production of H2O2. Both (13)C and (15)N SSNMR results show that Cu+ coordinates to Aβ(1-40) fibrils primarily through the side chain Nδ of both His-13 and His-14, suggesting major rearrangements from the Cu(2+) coordination via Nε in the redox cycle. (13)C SSNMR chemical-shifts analysis suggests that the overall Aβ conformations are largely unaffected by Cu(+)-binding. These results present crucial site-specific evidence of how the full-length Aβ in amyloid fibrils offers catalytic Cu(+)-centers.
    Journal of Biological Chemistry 02/2014; · 4.65 Impact Factor
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    ABSTRACT: Correlated networks of amino acids have been proposed to play a fundamental role in allostery and enzyme catalysis. These networks of amino acids can be traced from surface-exposed residues all the way into the active site, and disruption of these networks can decrease enzyme activity. Substitution of the distal Gly121 residue in E.coli dihydrofolate reductase results in up to a 200-fold decrease in the hydride transfer rate despite the fact that the residue is located 15 Å from the active-site center. In the present study, NMR relaxation experiments are used to demonstrate that dynamics on the ps-ns and μs-ms timescales are changed significantly in the G121V mutant of dihydrofolate reductase. In particular, ps-ns timescale dynamics are decreased in the FG loop (containing the mutated residue 121) and the neighboring active-site loop (the Met20 loop) in the mutant compared to wild-type enzyme, suggesting that these loops are dynamically coupled. Changes in methyl order parameters reveal a pathway by which dynamic perturbations can be propagated more than 25 Å across the protein from the site of mutation. All of the enzyme complexes, including the model Michaelis complex with folate and NADP(+) bound, assume an occluded ground state conformation, and we do not observe sampling of a higher energy closed conformation by (15)N R2 relaxation dispersion. This is highly significant, since it is only in the closed conformation that the cofactor and substrate reactive centers are positioned for reaction. The mutation also impairs μs - ms timescale fluctuations that have been implicated in product release from the wild type enzyme. Our results are consistent with an important role for Gly121 in controlling protein dynamics critical for enzyme function and further validate the dynamic energy landscape hypothesis of enzyme catalysis.
    Biochemistry 06/2013; · 3.38 Impact Factor
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    ABSTRACT: Model β-hairpin peptides based on variations in the turn sequence of Cochran's tryptophan zipper peptide, SWTWENGKWTWK, were studied using electronic circular dichroism (ECD), fluorescence, and infrared (IR) spectroscopies. The trpzip2 Asn-Gly turn sequence was substituted with Thr-Gly, Aib-Gly, (D)Pro-Gly, and Gly-Asn (trpzip1) to study the impact of turn stability on β-hairpin formation. Stability and conformational changes of these hairpins were monitored by thermodynamic analyses of the temperature variation of both FTIR (amide I') and ECD spectral intensities. These changes were fit to a two-state model which yielded different T(m) values, representing the folding/unfolding process, for hairpins with different β-turns. Different β-turns show systematic contributions to hairpin structure formation, and their inclusion in hairpin design can modify the folding pathways. Aib-Gly or (D)Pro-Gly sequences stabilize the turn resulting in residual Trp-Trp interaction at high temperatures, but at the same time the β-structure (cross strand H-bonds) can become less stable due to constraints of the turn, as seen for (D)Pro-Gly. The structure of the Aib-Gly turn containing hairpin was determined by NMR and was shown to be like trpzip2 (Asn-Gly turn) as regards turn and strand geometries, but to differ from trpzip1 (Gly-Asn turn). The Munoz and Eaton statistical mechanically derived multistate model, tested as an alternate point of view, represented contributions from H-bonds and hydrophobic interactions as well as conformational change as interdependent. Use of different spectral methods that vary in dependence on these physical interactions along with the structural variations provided insight to the complex folding pathways of these small, well-folded peptides.
    Proteins Structure Function and Bioinformatics 01/2012; 80(1):44-60. · 3.34 Impact Factor
  • Biophysical Journal 01/2012; 102(3):455-. · 3.67 Impact Factor
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    ABSTRACT: Cu(2+) binding to Alzheimer's β (Aβ) peptides in amyloid fibrils has attracted broad attention, as it was shown that Cu ion concentration elevates in Alzheimer's senile plaque and such association of Aβ with Cu(2+) triggers the production of neurotoxic reactive oxygen species (ROS) such as H(2)O(2). However, detailed binding sites and binding structures of Cu(2+) to Aβ are still largely unknown for Aβ fibrils or other aggregates of Aβ. In this work, we examined molecular details of Cu(2+) binding to amyloid fibrils by detecting paramagnetic signal quenching in 1D and 2D high-resolution (13)C solid-state NMR (SSNMR) for full-length 40-residue Aβ(1-40). Selective quenching observed in (13)C SSNMR of Cu(2+)-bound Aβ(1-40) suggested that primary Cu(2+) binding sites in Aβ(1-40) fibrils include N(ε) in His-13 and His-14 and carboxyl groups in Val-40 as well as in Glu sidechains (Glu-3, Glu-11, and/or Glu-22). (13)C chemical shift analysis demonstrated no major structural changes upon Cu(2+) binding in the hydrophobic core regions (residues 18-25 and 30-36). Although the ROS production via oxidization of Met-35 in the presence of Cu(2+) has been long suspected, our SSNMR analysis of (13)C(ε)H(3)-S- in M35 showed little changes after Cu(2+) binding, excluding the possibility of Met-35 oxidization by Cu(2+) alone. Preliminary molecular dynamics (MD) simulations on Cu(2+)-Aβ complex in amyloid fibrils confirmed binding sites suggested by the SSNMR results and the stabilities of such bindings. The MD simulations also indicate the coexistence of a variety of Cu(2+)-binding modes unique in Aβ fibril, which are realized by both intra- and intermolecular contacts and highly concentrated coordination sites due to the in-register parallel β-sheet arrangements.
    Journal of the American Chemical Society 02/2011; 133(10):3390-400. · 10.68 Impact Factor
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    ABSTRACT: The Trpzip2 peptide (WTWENGKWTWK-NH(2)), designed by Cochran and co-workers, contains two pairs of Trp's having cross-strand interaction and forms a stable antiparallel beta-hairpin. In order to study the geometries and effects on the structure and stability of different aromatic interactions, selected tryptophan residues were substituted with Tyr to get three Trpzip2 mutants with different Trp/Trp, Trp/Tyr, and Tyr/Tyr interacting pairs. Their native-state structures were determined using two-dimensional (2D) NMR and shown to have the same cross-strand edge-to-face Trp/Trp interaction as that in Trpzip2 for the Trp/Trp pair. The analogous Trp/Tyr and Tyr/Tyr pairs also tended to have an edge-to-face geometry. The effects of specific Trp/Trp, Trp/Tyr, and Tyr/Tyr interactions on hairpin stability were studied by varying temperature and monitoring structure with electronic circular dichroism (CD) and infrared (IR) absorption spectra. IR and CD temperature variations were fit to a two-state model that yielded lower T(m) values for Tyr containing mutants, indicating that Trp/Tyr and Tyr/Tyr interactions have less contribution to hairpin stability than the Trp/Trp interaction. Trp/Tyr interactions can provide significant stabilization, much greater than the Trp/aliphatic interaction, but Tyr/Tyr interactions are not as significant. Cross-strand interacting residues involving Trp with an edge-to-face orientation with Trp or Tyr had the strongest impact on hairpin stability.
    Biochemistry 06/2010; 49(22):4705-14. · 3.38 Impact Factor
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    ABSTRACT: Enzyme catalysis can be described as progress over a multi-dimensional energy landscape where ensembles of interconverting conformational substates channel the enzyme through its catalytic cycle. We applied NMR relaxation dispersion to investigate the role of bound ligands in modulating the dynamics and energy landscape of Escherichia coli dihydrofolate reductase to obtain insights into the mechanism by which the enzyme efficiently samples functional conformations as it traverses its reaction pathway. Although the structural differences between the occluded substrate binary complexes and product ternary complexes are very small, there are substantial differences in protein dynamics. Backbone fluctuations on the micros-ms timescale in the cofactor binding cleft are similar for the substrate and product binary complexes, but fluctuations on this timescale in the active site loops are observed only for complexes with substrate or substrate analog and are not observed for the binary product complex. The dynamics in the substrate and product binary complexes are governed by quite different kinetic and thermodynamic parameters. Analogous dynamic differences in the E:THF:NADPH and E:THF:NADP(+) product ternary complexes are difficult to rationalize from ground-state structures. For both of these complexes, the nicotinamide ring resides outside the active site pocket in the ground state. However, they differ in the structure, energetics, and dynamics of accessible higher energy substates where the nicotinamide ring transiently occupies the active site. Overall, our results suggest that dynamics in dihydrofolate reductase are exquisitely "tuned" for every intermediate in the catalytic cycle; structural fluctuations efficiently channel the enzyme through functionally relevant conformational space.
    Proceedings of the National Academy of Sciences 01/2010; 107(4):1373-8. · 9.81 Impact Factor
  • Biophysical Journal 01/2010; 98(3). · 3.67 Impact Factor
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    ABSTRACT: Raf kinase inhibitory protein (RKIP), also known as phoshaptidylethanolamine binding protein (PEBP), has been shown to inhibit Raf and thereby negatively regulate growth factor signaling by the Raf/MAP kinase pathway. RKIP has also been shown to suppress metastasis. We have previously demonstrated that RKIP/Raf interaction is regulated by two mechanisms: phosphorylation of RKIP at Ser-153, and occupation of RKIP's conserved ligand binding domain with a phospholipid (2-dihexanoyl-sn-glycero-3-phosphoethanolamine; DHPE). In addition to phospholipids, other ligands have been reported to bind this domain; however their binding properties remain uncharacterized. In this study, we used high-resolution heteronuclear NMR spectroscopy to screen a chemical library and assay a number of potential RKIP ligands for binding to the protein. Surprisingly, many compounds previously postulated as RKIP ligands showed no detectable binding in near-physiological solution conditions even at millimolar concentrations. In contrast, we found three novel ligands for RKIP that specifically bind to the RKIP pocket. Interestingly, unlike the phospholipid, DHPE, these newly identified ligands did not affect RKIP binding to Raf-1 or RKIP phosphorylation. One out of the three ligands displayed off target biological effects, impairing EGF-induced MAPK and metabolic activity. This work defines the binding properties of RKIP ligands under near physiological conditions, establishing RKIP's affinity for hydrophobic ligands and the importance of bulky aliphatic chains for inhibiting its function. The common structural elements of these compounds defines a minimal requirement for RKIP binding and thus they can be used as lead compounds for future design of RKIP ligands with therapeutic potential.
    PLoS ONE 01/2010; 5(5):e10479. · 3.53 Impact Factor
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    ABSTRACT: A series of beta-hairpin peptides based on variations of the TrpZip2 sequence, SWTWENGKWTWK, of Cochran and co-workers were studied using electronic circular dichroism (CD) and infrared (IR) spectra by varying temperature and pH. Selected tryptophan residues were substituted with Val to test the impact of specific Trp interactions on hairpin stability. Native-state structures of two of the variants were determined using 2-D NMR and shown to have the same cross-strand edge-to-face Trp-Trp interaction as in Trpzip2. Thermally induced conformational changes of the hairpins formed with these various sequences were studied with CD and IR. Thermodynamic analyses of the temperature variation of both IR (as analyzed using the amide I' frequency shift) and CD (intensity) spectra were fit to a two-state model that yielded different T(m) values, consistent with a multistate process of folding/unfolding. At low pH these differences were minimized, suggesting a change in the energetics. Cross-strand interacting Trp residues with an edge-to-face orientation had the strongest impact on hairpin stability, as judged by CD and IR data. The diagonal interaction between Trp2 and Trp9, which have a more parallel orientation in Trpzip2, contribute to the spectral response but do not independently stabilize the structure. Comparative study of these various physical interactions emphasizes the complex folding pathways that are important even for these small peptides.
    Biochemistry 09/2009; 48(43):10362-71. · 3.38 Impact Factor
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    ABSTRACT: C(alpha,alpha)-disubstituted amino acids (alphaalphaAAs) are widely used to conformationally constrain peptides. A series of pentapeptides containing dipropylglycine (Dpg) at alternating positions and their alpha-amino acid counterpart L-norvaline (Nva) analogues were synthesized to fully investigate the impact of Dpg on peptide backbone structure in aqueous solution. CD, VCD, and NMR spectral analysis suggest that Dpg containing peptides adopt more ordered structures relative to their Nva containing analogues. The central residues (Ala, Thr, Tyr, Val) and the charged side-chains of Glu and Lys play important roles in the degree of peptide folding. Hydrophobic and branched residues (Val, Tyr) at the central position of the peptide produce greater folding as judged by CD and NMR. Variation of the chemical shift with temperature (Deltadelta/DeltaT NH) of Ac-Glu-Dpg-Tyr-Dpg-Lys-NH(2) suggests a series of i --> i + 3 hydrogen bonds between the N-terminal acetyl carbonyl and the Tyr(3) NH, and the Glu(1) carbonyl and the Dpg(4) NH. The solution conformation of Ac-Glu-Dpg-Tyr-Dpg-Lys-NH(2) calculated from NMR-derived constraints shows a 3(10)-helical structure (two repetitive type-III beta-turns) at residues 1-4, which is supported by 2D NMR, CD, and VCD spectra. Analysis of NMR-derived models of these peptides suggest that there is a strong hydrophobic interaction of the pro-S propyl side chain of Dpg(2) and the Tyr(3) side-chain that may be a strong stabilizing force of the peptide folding in water.
    Biopolymers 06/2009; 92(5):452-64. · 2.88 Impact Factor
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    ABSTRACT: Conformational properties of a 12-residue tryptophan zipper (trpzip) beta-hairpin peptide (AWAWENGKWAWK-NH(2), a modification of the original trpzip2 sequence) are analyzed under equilibrium conditions using ECD and IR spectra of a series of variants, singly and doubly C(1)-labeled with (13)C on the amide CO. The characteristic features of the (13)CO component of the amide I' IR band and their sensitivity to the local structure of the peptide are used to differentiate stabilities for parts of the hairpin structure. Doubly labeled peptide spectra indicate that the ends of the beta-strands are frayed and that the center part is more stable as would be expected from formation of a stable hydrophobic core consisting of four tryptophan residues, and supported by MD simulations. NMR analyses were used to determine a best fit solution structure that is in close agreement with that of trpzip2, except for a small variation in the turn geometry. The distinct vibrational coupling patterns of the labeled sites based on this structure are also well matched by ab initio DFT-level calculations of their IR spectral patterns. Thermal unfolding of the peptides as studied with CD spectra could be fit with an apparent two-state transition model. ECD senses only the tryptophan interactions (tertiary-like) and their overall environment, as shown by TD-DFT modeling of the Trp-Trp pi-pi ECD. However, variation of the amide I IR spectra of (13)C-isotopomers showed that the thermal unfolding process is not cooperative in terms of the peptide backbone (secondary structure), since the transition temperatures sensed for labeled modes differ from those for the whole peptide. The thermal data also evidence dependence on concentration and pH but these cause little spectral variation. This study illustrates the consequences of multistate conformational change at the residue- or sequence-specific level in a system whose structure is dominated by hydrophobic collapse.
    The Journal of Physical Chemistry B 04/2009; 113(16):5661-74. · 3.61 Impact Factor
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    ABSTRACT: Raf kinase inhibitory protein (RKIP/PEBP1), a member of the phosphatidylethanolamine binding protein family that possesses a conserved ligand-binding pocket, negatively regulates the mammalian mitogen-activated protein kinase (MAPK) signaling cascade. Mutation of a conserved site (P74L) within the pocket leads to a loss or switch in the function of yeast or plant RKIP homologues. However, the mechanism by which the pocket influences RKIP function is unknown. Here we show that the pocket integrates two regulatory signals, phosphorylation and ligand binding, to control RKIP inhibition of Raf-1. RKIP association with Raf-1 is prevented by RKIP phosphorylation at S153. The P74L mutation increases kinase interaction and RKIP phosphorylation, enhancing Raf-1/MAPK signaling. Conversely, ligand binding to the RKIP pocket inhibits kinase interaction and RKIP phosphorylation by a noncompetitive mechanism. Additionally, ligand binding blocks RKIP association with Raf-1. Nuclear magnetic resonance studies reveal that the pocket is highly dynamic, rationalizing its capacity to interact with distinct partners and be involved in allosteric regulation. Our results show that RKIP uses a flexible pocket to integrate ligand binding- and phosphorylation-dependent interactions and to modulate the MAPK signaling pathway. This mechanism is an example of an emerging theme involving the regulation of signaling proteins and their interaction with effectors at the level of protein dynamics.
    Molecular and cellular biology 01/2009; 29(5):1306-20. · 6.06 Impact Factor
  • Biophysical Journal 01/2009; 96(3). · 3.67 Impact Factor
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    ABSTRACT: We previously determined the solution structures of the first 156 residues of human erythroid alpha-spectrin (SpalphaI-1-156, or simply Spalpha). Spalpha consists of the tetramerization site of alpha-spectrin and associates with a model beta-spectrin protein (Spbeta) with an affinity similar to that of native alpha- and beta-spectrin. Upon alphabeta-complex formation, our previous results indicate that there is an increase in helicity in the complex, suggesting conformational change in either Spalpha or Spbeta or in both. We have now used isothermal titration calorimetry, circular dichroism, static and dynamic light scattering, and solution NMR methods to investigate properties of the complex as well as the conformation of Spalpha in the complex. The results reveal a highly asymmetric complex, with a Perrin shape parameter of 1.23, which could correspond to a prolate ellipsoid with a major axis of about five and a minor axis of about one. We identified 12 residues, five prior to and seven following the partial domain helix in Spalpha that moved freely relative to the structural domain in the absence of Spbeta but when in the complex moved with a mobility similar to that of the structural domain. Thus, it appears that the association with Spbeta induced an unstructured-to-helical conformational transition in these residues to produce a rigid and asymmetric complex. Our findings may provide insight toward understanding different association affinities of alphabeta-spectrin at the tetramerization site for erythroid and non-erythroid spectrin and a possible mechanism to understand some of the clinical mutations, such as L49F of alpha-spectrin, which occur outside the functional partial domain region.
    Protein Science 12/2007; 16(11):2519-30. · 2.74 Impact Factor
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    ABSTRACT: Although the beta-rich self-assemblies are a major structural class for polypeptides and the focus of intense research, little is known about their atomic structures and dynamics due to their insoluble and noncrystalline nature. We developed a protein engineering strategy that captures a self-assembly segment in a water-soluble molecule. A predefined number of self-assembling peptide units are linked, and the beta-sheet ends are capped to prevent aggregation, which yields a mono-dispersed soluble protein. We tested this strategy by using Borrelia outer surface protein (OspA) whose single-layer beta-sheet located between two globular domains consists of two beta-hairpin units and thus can be considered as a prototype of self-assembly. We constructed self-assembly mimics of different sizes and determined their atomic structures using x-ray crystallography and NMR spectroscopy. Highly regular beta-sheet geometries were maintained in these structures, and peptide units had a nearly identical conformation, supporting the concept that a peptide in the regular beta-geometry is primed for self-assembly. However, we found small but significant differences in the relative orientation between adjacent peptide units in terms of beta-sheet twist and bend, suggesting their inherent flexibility. Modeling shows how this conformational diversity, when propagated over a large number of peptide units, can lead to a substantial degree of nanoscale polymorphism of self-assemblies.
    Proceedings of the National Academy of Sciences 12/2006; 103(47):17753-8. · 9.81 Impact Factor
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    ABSTRACT: We used nuclear magnetic resonance relaxation dispersion to characterize higher energy conformational substates of Escherichia coli dihydrofolate reductase. Each intermediate in the catalytic cycle samples low-lying excited states whose conformations resemble the ground-state structures of preceding and following intermediates. Substrate and cofactor exchange occurs through these excited substates. The maximum hydride transfer and steady-state turnover rates are governed by the dynamics of transitions between ground and excited states of the intermediates. Thus, the modulation of the energy landscape by the bound ligands funnels the enzyme through its reaction cycle along a preferred kinetic path.
    Science 10/2006; 313(5793):1638-42. · 31.20 Impact Factor
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    ABSTRACT: Solid-state NMR has been used to analyze the chemical environments of sodium sites in powdered crystalline samples of sodium nucleotide complexes. Three of the studied complexes have been previously characterized structurally by crystallography (disodium deoxycytidine-5'-monophosphate heptahydrate, disodium deoxyuridine-5'-monophosphate pentahydrate and disodium adensoine-5'-triphosphate trihydrate). For these salts, the nuclear quadrupole coupling parameters measured by (23)Na multiple-quantum magic-angle-spinning NMR could be readily correlated with sodium ion coordination environments. Furthermore, two complexes that had not been previously characterized structurally, disodium uridine-3'-monophosphate and a disodium uridine-3'-monophosphate/disodium uridine-2'-monophosphate mix, were identified by solid-state NMR. A spectroscopic assignment of the four sites of an additional salt, disodium adensoine-5'-triphosphate trihydrate, is also presented and discussed within the context of creating a general approach for the spectroscopic assignment of multiple sites in sodium nucleotide complexes.
    Magnetic Resonance in Chemistry 04/2006; 44(3):366-74. · 1.53 Impact Factor
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    ABSTRACT: The local dynamics of aromatic cores was analyzed for a homologous series of polyamides in the solid phase incorporating phenyl, biphenyl and naphthyl groups. Preliminary wide-line and spin-relaxation variable-temperature (1)H NMR measurements revealed the presence of thermally activated molecular motions for each polymer studied. A number of (13)C NMR experiments were then implemented to further clarify the nature and extent of such motions. These included (1)H-(13)C 2D separate-local-field measurements, whose line shapes revealed that motions involved for all cases a superposition of states. These could in principle be associated with rigid and mobile populations in these semi-crystalline aramides, a model that yielded a proper description of the spectra at all temperatures. To further probe this model the relaxation behavior of the aramides'(13)C spins was monitored in the rotating frame as a function of temperature, in both the presence and absence of homonuclear (1)H-(1)H decoupling. The variations observed in these measurements evidenced a thermally activated, relatively broad distribution of motional rates in the polymers. Editing the 2D local-field data according to the (13)C relaxation also supported this heterogeneous dynamic model. The mechanism underlying this behavior and implications towards the (13)C analysis of motions in aramides in particular and complex polymers in general, is briefly discussed.
    Solid State Nuclear Magnetic Resonance 03/2006; 29(1-3):132-41. · 2.10 Impact Factor

Publication Stats

654 Citations
136.81 Total Impact Points

Institutions

  • 2005–2013
    • The Scripps Research Institute
      • Department of Cell and Molecular Biology
      La Jolla, California, United States
  • 2000–2012
    • University of Illinois at Chicago
      • Department of Chemistry
      Chicago, IL, United States
  • 2006–2010
    • University of Chicago
      • Department of Biochemistry & Molecular Biology
      Chicago, Illinois, United States
    • Cancer Research Institute
      New York City, New York, United States
    • University of California, San Diego
      • Department of Chemistry and Biochemistry
      San Diego, CA, United States
  • 2009
    • University of Colorado at Boulder
      Boulder, Colorado, United States