Quantitative Analysis of Hydrophobically Induced Folding in a Minimal Model System

Gardner, Robb R.; Christianson, Laurie A.; Gellman, Samuel H.

doi:10.1021/ja970531w

Cited by 45 publications

(48 citation statements)

References 12 publications

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“…2.22 [122] demonstrate that, in line with the results discussed above with the balance (Fig. 2.20) [120,121], hydrophobic contributions of aliphatic groups are small in comparison to substituents bearing electron lone pairs or multiple bonds. In accordance with this observation, benzoate has a much larger affinity to positively charged, water-soluble porphyrins than does cyclohexane-carboxylate, even though the latter has the same surface size and is more hydrophobic [42 c].…”

Section: Dispersive Interactionssupporting

confidence: 80%

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Introduction to Molecular Recognition Models

Schneider¹

2003

Methods and Principles in Medicinal Chemistry

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Introduction and ScopeMolecular recognition is the basis of both biological systems and many chemical technologies. When Emil Fischer in 1894 put forward the first model for molecular recognition in the form of his famous lock-and-key principle, he could not anticipate that chemists would one day produce fully synthetic systems of this kind. It took almost 100 years until completely artificial complexes were developed, in which a host molecule embraces a guest molecule in the way that Fischer believed to be the basis of enzyme function. In 1987 the Nobel Prize award to Cram, Lehn, and Pedersen highlighted how far chemistry had gone in these directions. In recent decades, the field, which Cram named "host-guest chemistry," and Lehn called "supramolecular chemistry," has experienced a virtual explosion (see monographs [1-8]). Countless groups over the world are now synthesizing host structures with intricate binding properties for a large array of targets and analyzing supramolecular complexes with rapidly developing physical methods. Coordination chemistry is traditionally directed towards transition metal ion complexation but can provide much additional, and sometimes overlooked, information on principles ruling the spontaneous formation of host-guest complexes.Empirical analyses of structures and energetics in synthetic supramolecular complexes can provide insight into the non-covalent interaction mechanisms and attribute energy values to each of them. Much of the principles and quantitative information learned from these complexes can be of use for the understanding of biological systems and, e.g., the design of bioactive ligands. Most of the efforts in modern supramolecular chemistry are of course directed towards new technologies in separation, sensors, materials, information storage and processing, energy conversion, artificial enzymes, etc. At the same time, these systems provide many new models for molecular recognition processes and a wealth of information on the underlying interactions. Synthetic chemistry is able to deliver biomimetic as well as unnatural host compounds in which every desired function can be implemented. These functions can be directed towards any given substrate site and can be designed to work in any environment, be it in the ground state or the transition state.

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Section: Dispersive Interactionssupporting

confidence: 80%

“…The underlying energy components are experimentally accessible in principle by measurements with conformational balances such as those shown in Fig. 2.21 [120]. For the substituent R = H, one observes the same small preference DG E/Z for the E conformer in water (D 2 O) as in chloroform.…”

Section: Dispersive Interactionsmentioning

confidence: 93%

Introduction to Molecular Recognition Models

Schneider¹

2003

Methods and Principles in Medicinal Chemistry

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“…A similar methylene chemical shift pattern was observed for the E and Z rotamers of six analogues of 1a, suggesting that this trend is general. 4 For 3a, the major rotamer methylene resonances are more closely spaced than are the minor rotamer methylene resonances, which leads to our assignment of the major rotamer as Z. Ester 3b in CDCl 3 at 297 K displayed a major and minor set of 1 H resonances that were attributed to Z and E rotamers; the minor rotamer accounted for 6% of the population. The 4-fold increase in E rotamer population for 3a in D 2 O relative to 3b in CDCl 3 supports the conclusion that the E rotamer of 3a is favored in aqueous solution by a hydrophobic effect.…”

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confidence: 85%

“…For 1b and a series of related diesters with varying hydrocarbon side chains on the R-amino acid residue, K EZ ) 1.6 ( 0.1 in chloroform. 4 In contrast, K EZ values vary significantly among dicarboxylates in water;…”

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confidence: 98%

Solvent-Dependent Stabilization of the E Configuration of Propargylic Secondary Amides

2000

Self Cite

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Secondary amides typically exist 98-99% in the Z rotamer to avoid steric repulsion between the substituent on the carbonyl carbon and the nitrogen. In contrast, secondary amide 3a displays 24% E rotamer at room temperature in aqueous solution. The analogous ester displays 6% E rotamer in chloroform, which suggests that the relatively high E conformer population observed for 3a in water results in part from the low steric bulk of the sp-hybridized carbons and in part from the hydrophobic effect.

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“…It is therefore inconsistent to invoke functional group polarity as an explanation for the observed gap in binding enthalpy. A possible clue to the underlying reason for this difference can be found in the work of Gellman et al, [17] which indicates that the association between two aromatic components is energetically more favorable than a similar interaction between aliphatic and aromatic constituents. Further supporting evidence is provided by investigations of protein structure by Makhatadze and Privlalov [18] which indicates that the enthalpy of the van der Waals interactions is indeed higher for aromatic components (180 J mol À1…”

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confidence: 99%

Highly Organized Spherical Hosts That Bind Organic Guests in Aqueous Solution with Micromolar Affinity: Microcalorimetry Studies

Piatnitski

Flowers

Deshayes³

2000

Chem. Eur. J.

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Two novel closed-shell hemicarcerand-like hosts with spherical cavities of 11 A diameter that are soluble in aqueous solution were constructed. The binding of xylenes, aryl ethers, polyaromatic compounds, ferrocene derivatives, and bicyclic aliphatic compounds were examined by NMR spectroscopy and microcalorimetry. NMR binding studies indicated that binding depended upon guest hydrophobicity and shape. No binding was detected for guests in which a charge must be desolvated as part of inclusion or for guests that can not fit within the cavity of the host. Three complexes 2.naphthalene, 2.p-xylene, and 2.ferrocene were isolated and found to be indefinitely stable in the solid phase and in aqueous solution. The binding constants for these complexes are estimated to be greater than 10(8) M-1. Thirteen guests were examined by microcalorimetry with binding constants ranging between 10(7) and 10(3) M-1. A comparison of results obtained here with those from previous work with beta-cyclodextrin and cyclophane hosts, along with analysis of the entropy-enthalpy compensation data, indicate that there is a higher degree of guest desolvation with this host structure than with open-shell hosts. This accounts at least partially for the increase in affinity observed with these closed-shell hosts. Replacing a hydroxy group in the host portal with a hydrogen atom does not affect the binding constant, a finding consistent with the guest residing deeply buried within the host cavity. It was observed that aromatic guests are bound with higher affinity than aliphatic ones in agreement with results that point to the importance of London dispersion forces in the association of aromatic components in face-to-edge orientations. The correlation of changes in NMR chemical shift with microcalorimetry data supports a model in which increased CH-pi interactions strengthen association between host and guest due to the dominant role of van der Waals dispersion forces. Remarkably, the binding constant for the 1,4 isomer of dimethoxybenzene is 32 times higher than for the 1,2 isomer, and even greater discrimination is observed between the xylene guests since the binding constant for p-xylene is 80 times greater than that for o-xylene. This discrimination between isomeric guests by a rigid host indicates that changes in specific hydrophobic interactions have substantial effects upon binding affinity.

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Quantitative Analysis of Hydrophobically Induced Folding in a Minimal Model System

Cited by 45 publications

References 12 publications

Introduction to Molecular Recognition Models

Introduction to Molecular Recognition Models

Solvent-Dependent Stabilization of the E Configuration of Propargylic Secondary Amides

Highly Organized Spherical Hosts That Bind Organic Guests in Aqueous Solution with Micromolar Affinity: Microcalorimetry Studies

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