Equilibrium constants for association of guanidinium and ammonium ions with oxyanions

Springs, Bleecker; Haake, Paul

doi:10.1016/0045-2068(77)90019-0

Cited by 122 publications

(124 citation statements)

References 11 publications

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“…Ion pairing between guanidinium+ and carboxylate-ions is strong enough to detect in bimolecular reactions between model compounds, in which K is =o0.4 M-' (27,28 (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

A salt bridge stabilizes the helix formed by isolated C-peptide of RNase A.

Bierzyński¹,

Kim²,

Baldwin³

1982

Proc. Natl. Acad. Sci. U.S.A.

276

187

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C-peptide, which contains the 13 NH2-terminal residues of RNase A, shows partial helix formation in water at low temperature (1C, pH 5, 0.1 M NaCI), as judged by CD spectra; the helix is formed intramolecularly [Brown, J. E. & Klee, W. A. (1971) Biochemistry 10, 470-476]. We find that helix stability depends strongly on pH: both a protonated histidine (residue 12) and a deprotonated glutamate (residue 9 or 2 or both) are required for optimal stability. This information, together with model building, suggests that the salt bridge Glu-9 His-12+ stabilizes the helix. Formationofthehelixisenthalpydriven [van'tHoff AH, -16kcal/ mol (1 cal = 4.18 J)] and the helix is not observed above 30C.Proton NMR data indicate that several side chains adopt specific conformations as the helix is formed. These results have two implications for the mechanism of protein folding. First, they indicate that short at-helices, stabilized by specific side-chain interactions within the helix, can be stable enough in water to function as folding intermediates. Second, they suggest that similar experiments with peptides of controlled amino acid sequence could be used to catalogue the intrahelix interactions that stabilize or destabilize a-helices in aqueous solution. These data might provide the code relating amino acid sequence to the locations of a-helices in proteins.Short a-helices, of the size range usually found in globular proteins (6-20 residues), are highly unstable in water in the absence of specific stabilizing interactions, according to data obtained with random copolymers by the "host-guest" technique (1). For short helices (n < 20) and for o << 1, the ratio ofhelical to nonhelical residues depends on the quantity 0,rn-l/(S -1)2 (see Note Added in Proof), where o is the helix nucleation constant, s is an average stability constant for one residue, and n is the number of H-bonded residues in the helix. Values of s vary from 0.5 to 1.3 for different amino acid residues at 0-60TC, while o is estimated to be~-'10`(1), so that the fraction of molecules in helical form is expected to be 10`for a short helix. Most studies of helix formation by protein fragments agree with this deduction. The three cyanogen bromide peptides of sperm whale myoglobin give CD spectra that indicate that very little a-helix is present in water at 250C, although partly helical spectra are obtained in 95% methanol (2). The conclusion has been drawn that tertiary interactions are needed to stabilize the a-helices of globular proteins in water.An exception was found by Brown and Klee (3): C-peptide of RNase A has a CD spectrum indicative of partial helix formation in water at 10C. They found that the helix forms monomolecularly, is unstable at 260C, and is unstable in deionized water. Molecular weight measurements by sedimentation equilibrium showed that C-peptide is monomeric at concentrations up to 1 mM under conditions in which helix formation occurs (10C; ionic strength, 0.1 M). Freedom from aggregation at moderate concentration is an important prop...

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“…Ion pairing between guanidinium+ and carboxylate-ions is strong enough to detect in bimolecular reactions between model compounds, in which K is =o0.4 M-' (27,28 (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

A salt bridge stabilizes the helix formed by isolated C-peptide of RNase A.

Bierzyński¹,

Kim²,

Baldwin³

1982

Proc. Natl. Acad. Sci. U.S.A.

276

187

View full text Add to dashboard Cite

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“…These proved to be very effective transporters. For example, the carbamate 9-mer 6 (n=9) translocates into cells 2.3 times faster than the D-arg 9-mer (4, n=9) which itself is taken up into cells approximately three times faster than Tat [49][50][51][52][53][54][55][56][57] . While many studies address only cellular uptake, this study also showed that the oligocarbamate transporters penetrate mouse skin, a finding of much significance as the skin represents a much more formidable barrier than the plasma membrane and is the key barrier for many dermatological applications.…”

Section: Linear Grtsmentioning

confidence: 99%

“…The driving force for this pairing is the associated decrease in free energy in going from solution to the surface of a membrane. While a guanidinium group has no recognizable hydration shell [51] and a very weak association with a counterion such as a phosphate group in an aqueous environment (~ 0.2 kcal/mol) [52], as the guanidinium group approaches the surface of a lipid bilayer and local polarity decreases, its association with a phosphate counterion increases dramatically (~2.6 -6.0 kcal/mol) [53]. This association is further strengthened as the complex moves into the less polar membrane.…”

Section: Associationmentioning

confidence: 99%

“…It is noteworthy mechanistically that the enhanced uptake observed when the number of guanidinium groups was increased to 9 is similar to that found with peptoids. To investigate the localization of the conjugates, the authors also treated HeLa S3 cells individually with G9-Fl (14), G9-GFP, and Tat (49)(50)(51)(52)(53)(54)(55)(56)(57) -GFP. The cells were fixed and visualized by deconvolution microscopy.…”

Section: Dendrimeric and Branched Grtsmentioning

confidence: 99%

“…Structure-function relationships of fluorescently labeled peptides inspired by Tat [49][50][51][52][53][54][55][56][57] In 1996, we started a program directed at designing molecular transporters that would be superior to the Tat 9-mer (RKKRRQRRR or Tat [49][50][51][52][53][54][55][56][57] ) in performance and in cost, thereby allowing for broader exploitation of transporter-based drug delivery for therapeutic applications. Our selection of the Tat 9-mer as a starting point relative to other transporter leads was influenced by the rather paradoxical but potentially therapeutically valuable behavior of this lead: it is highly polar and thus readily soluble in water -a factor that could be exploited in therapeutic administration -but unlike most polar systems it readily passes through the nonpolar membrane of cells.…”

Section: Design and Synthesis Of Guanidinium-rich Transporters (Grts)mentioning

confidence: 99%

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The design of guanidinium-rich transporters and their internalization mechanisms

Wender

Galliher

Goun

et al. 2008

Advanced Drug Delivery Reviews

380

337

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The ability of a drug or probe to cross a biological barrier has historically been viewed to be a function of its intrinsic physical properties. This view has largely restricted drug design and selection to agents within a narrow log P range. Molecular transporters offer a strategy to circumvent these restrictions. In the case of guanidinium-rich transporters (GRTs), a typically highly water-soluble conjugate is found to readily pass through the non-polar membrane of a cell and for some across tissue barriers. This activity opens a field of opportunities for the use of GRTs to enable delivery of polar and nonpolar drugs or probes as well as to enhance uptake of those of intermediate polarity. The field of transporter enabled or enhanced uptake has grown dramatically in the last decade. Some GRT drug conjugates have been advanced into clinical trials. This review will provide an overview of recent work pertinent to the design and mechanism of uptake of GRTs.

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