Carbon-13 nuclear magnetic resonance study of the motional behavior of ethyl isocyanide bound to myoglobin and hemoglobin

Gilman, J. G.

doi:10.1021/bi00578a022

Cited by 11 publications

(2 citation statements)

References 28 publications

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“…With this hydrated volume the rotational correlation time of 28 ns is calculated for a sphere in water of 0.01 P at 20 °C by using the formula: tr = 1 /6DR = i)V/kT. This value is to be compared with the experimental values of 26 ± 2 ns at 20 °C from electron spin resonance measurements on spin-labeled hemoglobin (McCalley et al, 1972), 28 ns at 25 °C from dielectric relaxation measurements (Oncley, 1938), and 39 ± 7 ns at 31 °C from nuclear magnetic resonance (NMR) longitudinal relaxation times of the a-carbon envelopes (Gilman, 1979). In the NMR measurements the 1.8-fold increase in solution viscosity produced by the high (8-9 mM in heme) hemoglobin concentrations (Ross & Minton, 1977) should significantly increase the rotational correlation time.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of the quaternary conformational change in trout hemoglobin

Hofrichter¹,

Henry²,

Szabó³

et al. 1991

Biochemistry

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The kinetics of conformational changes in trout hemoglobin I have been characterized over the temperature range 2-65 degrees C from time-resolved absorption spectra measured following photodissociation of the carbon monoxide complex. Changes in the spectra of the deoxyheme photoproduct were used to monitor changes in the protein conformation. Although the deoxyheme spectral changes are only about 8% of the total spectral change due to ligand rebinding, a combination of high-precision measurements and singular value decomposition of the data permits a detailed analysis of both their amplitudes and relaxation rates. Systematic variation of the degree of photolysis was used to alter the distribution of liganded tetramers, permitting the assignment of the spectral relaxation at 20 microseconds to the R----T quaternary conformational change of the zero-liganded and singly liganded molecules and spectral relaxations at about 50 ns and 2 microseconds to tertiary conformational changes within the R structure. Analysis of the effect of photoselection by the linearly polarized excitation pulse indicates that a major contribution to the apparent geminate rebinding in the 50-ns relaxation arises from rotational diffusion of molecules containing unphotolyzed heme-CO complexes. The activation enthalpy and activation entropy for the R0----T0 transition are +7.4 kcal/mol and -12 cal mol-1 K-1. Using the equilibrium data, delta H = +29.4 kcal/mol and delta S = +84.4 cal mol-1 K-1 [Barisas, B. G., & Gill, S. J. (1979) Biophys. Chem. 9, 235-244], the activation parameters for the T0----R0 transition are calculated to be delta H = +37 kcal/mol and delta S = +73 cal mol-1 K-1. The similarity of the equilibrium and activation parameters for the T0----R0 transition indicates that the transition state is much more R-like than T-like. This result suggests that in the path from T0 to R0 the subunits have already almost completely rearranged into the R configuration when the transition state is reached, while in the path from R0 to T0 the subunits remain in a configuration close to R in the transition state. The finding of an R-like transition state explains why the binding of ligands causes much smaller changes in the R----T rates than in the T----R rates.

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Section: Discussionmentioning

confidence: 99%

Dynamics of the quaternary conformational change in trout hemoglobin

Hofrichter¹,

Henry²,

Szabó³

et al. 1991

Biochemistry

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“…Linus Pauling was the first to demonstrate the ability of alkyl isocyanides to interact with hemoglobin by competing with oxygen and respecting the same cooperative effect. − He also demonstrated marked differences of different alkyl isocyanides for their ability to interact with the hemoglobin because of steric hindrance at the heme pocket. Ethyl isocyanide, isopropryl isocyanide and tert -butyl isocyanide were evaluated both on free heme and in hemoglobin.…”

Section: Interaction With Metalloproteinsmentioning

confidence: 99%

Medicinal Chemistry of Isocyanides

et al. 2021

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In eons of evolution, isocyanides carved out a niche in the ecological systems probably thanks to their metal coordinating properties. In 1859 the first isocyanide was synthesized by humans and in 1950 the first natural isocyanide was discovered. Now, at the beginning of XXI century, hundreds of isocyanides have been isolated both in prokaryotes and eukaryotes and thousands have been synthesized in the laboratory. For some of them their ecological role is known, and their potent biological activity as antibacterial, antifungal, antimalarial, antifouling, and antitumoral compounds has been described. Notwithstanding, the isocyanides have not gained a good reputation among medicinal chemists who have erroneously considered them either too reactive or metabolically unstable, and this has restricted their main use to technical applications as ligands in coordination chemistry. The aim of this review is therefore to show the richness in biological activity of the isocyanidecontaining molecules, to support the idea of using the isocyanide functional group as an unconventional pharmacophore especially useful as a metal coordinating warhead. The unhidden hope is to convince the skeptical medicinal chemists of the isocyanide potential in many areas of drug discovery and considering them in the design of future drugs.

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A critical evaluation of models for complex molecular dynamics: Application to NMR studies of double‐ and single‐stranded DNA

et al. 1983

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SynopsisThe nature of internal and overall motions in native (double-stranded) and denatured (single-stranded) DNA fragments 120-160 base pairs (bp) long is examined by moleculardynamics modeling using 13C-nmr spin-relaxation data obtained over the frequency range of 37-125 MHz. The broad range of I3C frequencies is required to differentiate among various models. Relatively narrow linewidths, large nuclear Overhauser enhancements (NOES), and short T1 values all vary significantly with frequency and indicate the presence of rapid, restricted internal motions on the nanosecond time scale. For double-stranded DNA monomer fragments (147 bp, 24 8, diam a t 32"C), the overall motion is that of an axially symmetric cylinder ( r x = -lop6 s; 7, = -1.8 X s), which is in good agreement with values calculated from hydrodynamic theory ( T~ = -1.8 X s). The DNA internal motion can be modeled as restricted amplitude internal diffusion of individual C-H vectors of deoxyribose methine carbons Cl', C3', and C4', either with conic boundary conditions (7, = -4 X 10-9 s, Ocone = -21O) or as a bistable jump ( T A = T B = -2 X s, O = -15"). We discuss the critical role in molecular-dynamics modeling played by the angle (p) that individual C-H vectors make with the long axis of the DNA helix. Eeat denaturation brings about increases in both the rute and amplitude of the internal motion (described by the wobble model with rW = -0.2 X s, O,,,, = -50' 1, and overall motion is affected by becoming essentially isotropic ( T~ = T~ = -5 X s) for the single-stranded molecules. Since '3C-nmr data obtained at various DNA concentrations for C2' of the deoxyribose ring is not described weli by the above models, a new model incorporating an additional internal motion is proposed to take into account the rapid, extensive, and weakly coupled motion of C2'. s; T~ = -2.7 X

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Carbon-13 nuclear magnetic resonance study of the motional behavior of ethyl isocyanide bound to myoglobin and hemoglobin

Cited by 11 publications

References 28 publications

Dynamics of the quaternary conformational change in trout hemoglobin

Dynamics of the quaternary conformational change in trout hemoglobin

Medicinal Chemistry of Isocyanides

A critical evaluation of models for complex molecular dynamics: Application to NMR studies of double‐ and single‐stranded DNA

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