The properties of disordered proteins are thought to depend on intrinsic conformational propensities for polyproline II (PP II) structure. While intrinsic PP II propensities have been measured for the common biological amino acids in short peptides, the ability of these experimentally determined propensities to quantitatively reproduce structural behavior in intrinsically disordered proteins (IDPs) has not been established. Presented here are results from molecular simulations of disordered proteins showing that the hydrodynamic radius (R h) can be predicted from experimental PP II propensities with good agreement, even when charge-based considerations are omitted. The simulations demonstrate that R h and chain propensity for PP II structure are linked via a simple power-law scaling relationship, which was tested using the experimental R h of 22 IDPs covering a wide range of peptide lengths, net charge, and sequence composition. Charge effects on R h were found to be generally weak when compared to PP II effects on R h. Results from this study indicate that the hydrodynamic dimensions of IDPs are evidence of considerable sequence-dependent backbone propensities for PP II structure that qualitatively, if not quantitatively, match conformational propensities measured in peptides.

Intrinsically disordered proteins are proteins that do not show a set three‐dimensional tertiary structure and are usually involved in signal‐transduction and transcription regulation. It is estimated that upwards of 33% of all eukaryotic proteins contain intrinsically disordered domains. It is known that hydrodynamic radius (Rh) of IDPs depends largely on their intrinsic propensity to conform into a polyproline‐II helix. A generalized understanding of the molecular organization of IDPs in response to perturbations is presented here. This model uses polyproline‐II propensities and net charge in order to simulate Rh and understand the structural properties of IDPs in terms of discrete changes in a system. Fundamental understanding of protein structures in IDPs may provide an avenue for novel drug design, diagnostics, and treatment.Support or Funding InformationResearch reported in this poster was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award R15GM115603.

Cyclic voltammetry (CV) and controlled-potential electrolysis (CPE) were employed to examine the reactions of electrogenerated ligand-reduced nickel(II) salen with benzyl bromide, 1-bromomethylnaphthalene, and alpha-bromodiphenylmethane. Cyclic voltammo-grams for nickel(II) salen in the presence of benzyl bromide or 1-bromomethylnaphthalene exhibit characteristic features for the catalytic reduction of substrates involving radical intermediates. Bulk electrolyses of benzyl bromide and 1-bromomethylnaphthalene at carbon cathodes catalyzed by nickel(II) salen were also carried out at selected potentials to afford various products. These results were compared with similar reaction involving 1-bromooctane as the substrate. Further comparison of the CVs for nickel(II) salen before and after reactions with the four different organic halides reveals that the steric effect could play an important role in the corresponding nucleophilic attack of the substrates by ligand-reduced catalyst (a radical-anion), which follows the sequence of 1-bromooctane > benzyl bromide > 1-bromomethylnaphthalene > alpha-bromodiphenylmethane in terms of reaction efficiency. Moreover, theoretical calculations using density functional theory were carried out to establish a proposed mechanism for the electrochemical reactions on the basis of previous and current studies. (C) The Author(s) 2015. Published by ECS.

Nickel salen catalysts have been extensively used for the electrochemical reduction of various organic halides. In general, nickel(II) salen (1) would undergo one-electron reduction to generate either the metal-reduced nickel(I) salen (2) or the ligand-centered radical-anion (3, Scheme 1), which can subsequently transfer an electron to the organic halide substrate to produce a radical and a halide ion (1-3). In this catalytic process, the ligand-reduced nickel salen (3) may also react with alkyl halide to form a nickel(II) salen that is alkylated at the imino bonds of the ligand (2,3). Nevertheless, when the sterically hindered dimethylated nickel(II) salen is employed as the catalyst, the corresponding alkylation reaction could be minimized (4). In this study, nickel salen-catalyzed reduction of benzyl bromide and 1-bromomethylnaphthalene was examined by cyclic voltammetry (CV) and controlled-potential electrolysis (CPE) for comparison. Furthermore, 1-bromooctane and bromodiphenylmethane were also used as the substrates for the reaction with electrochemically reduced nickel salen species (2 and 3). The results show that the reaction of ligand-reduced nickel salen (3) with organic halides can be significantly affected by the substrate structure due to steric effects. Fig. 1 depicts the CVs recorded at a scan rate of 100 mV s–1 for the reduction of nickel(II) salen in the presence of four different concentrations of benzyl bromide in dimethylformamide (DMF) containing 0.050 M tetramethylammonium tetrafluoroborate (TMABF4). As shown by curves B-E, the first cathodic peak is approximately 100-150 mV more positive than that for reduction of nickel(II) salen by itself (curve A), attributed to the catalytic cleavage of carbon-bromine bond of the substrate. The magnitude of this peak increases with the substrate concentration and eventually it merges with the reduction peak of nickel salen (second cathodic wave at -1.70 V). Moreover, the anodic peak due to oxidation of nickel(I) salen disappears. These features are generally characteristic of the catalytic reduction of organic halides (3,4). Large scale electrolysis of 20 mM benzyl bromide with 2.0 mM nickel salen at reticulated vitreous carbon electrodes held at -1.55 V gives toluene, bibenzyl, and benzyl ether as the major products in a total yield of 94%, which is higher than that for the catalytic reduction of 1-bromooctane (86%) (5), suggesting the reaction of 3 with benzyl bromide should be less prominent than with 1-bromooctane to form the alkylated nickel salen. Similar CV and CPE results were obtained for the catalytic reduction of 1-bromomethylnaphthalene, mostly due to steric effect caused by the bulky substrate. Additionally, the reactivity of electrogenerated ligand-reduced nickel salen (3) towards the four organic halides follows the sequence of 1-bromooctance > benzyl bromide > 1-bromomethylnaphthalene > bromodiphenylmethane, as revealed by Fig. 2. The alkylation of 3 diminishes as the substrate molecules turn to be more bulky and therefore sterically hinder the corresponding nucleophilic reactions (4,5). References Miranda, J. A.; Wade, C. J.; Little, R. D. J. Org. Chem. 2005, 70, 8017-8026. Goken, D. M.; Peters, D. G.; Karty, J. A.; Reilly, J. P. J. Electroanal. Chem. 2004, 564, 123-132. Raess, P. W,; Mubarak, M. S.; Ischay, M. A.; Foley, M. P.; Jennermann, T. B.; Raghavachari, K.; Peters, D. G. J. Electroanal. Chem. 2007, 603, 124-134. Foley, M. P.; Du, P.; Griffith, K. J.; Karty, J. A.; Mubarak, M. S.; Raghavachari, K.; Peters, D. G. J. Electroanal. Chem. 2010, 647, 194-203. Ji, C.; Day, S. E.; Silvers, W. C. J. Electroanal. Chem. 2008, 622, 15-21.