Synthesis and NMR Analysis of a Conformationally Controlled β-Turn Mimetic Torsion Balance

Lypson, Alyssa B.; Wilcox, Craig S.

doi:10.1021/acs.joc.6b02307

Cited by 10 publications

(13 citation statements)

References 69 publications

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“…Thes trength of intramolecular interactions can be assessed using conformational reporters that act as molecular balances. [10,13] Them olecular balances employed in the present study are based on previous designs that enabled the measurement of solvent and substituent effects on intramolecular interactions (Figure 2A). [14] Thep osition of the conformational equilibrium in these new balances enables measurement of the energy of the Hbond at the end of alinear chain of one,two,orthree Hbonds.These molecular balances were synthesized and found to exist in two conformational states on the NMR timescale at room temperature (see the Supporting Information for NMR spectra and minimized structures).…”

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confidence: 99%

Strong Short‐Range Cooperativity in Hydrogen‐Bond Chains

et al. 2017

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Chains of hydrogen bonds such as those found in water and proteins are often presumed to be more stable than the sum of the individual H bonds. However, the energetics of cooperativity are complicated by solvent effects and the dynamics of intermolecular interactions, meaning that information on cooperativity typically is derived from theory or indirect structural data. Herein, we present direct measurements of energetic cooperativity in an experimental system in which the geometry and the number of H bonds in a chain were systematically controlled. Strikingly, we found that adding a second H‐bond donor to form a chain can almost double the strength of the terminal H bond, while further extensions have little effect. The experimental observations add weight to computations which have suggested that strong, but short‐range cooperative effects may occur in H‐bond chains.

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confidence: 99%

Strong Short‐Range Cooperativity in Hydrogen‐Bond Chains

et al. 2017

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“…Lypson and Wilcox reported a new molecular balance for the assessment of pairwise amino acid interactions in antiparallel β‐sheets (Figure ) . They aimed at optimising the mutual arrangement of the amino acid chains attached to aromatic rings to control hydrogen bond formation, although the molecular balance considered is relatively complex in terms of a large number of conformations it could potentially adopt.…”

Section: Other Balancesmentioning

confidence: 99%

“…Lypson and Wilcoxr eported an ew molecular balance for the assessment of pairwise amino acid interactions in antiparallel b-sheets ( Figure 22). [41] They aimed at optimising the mutual arrangement of the amino acid chains attached to aromatic rings to control hydrogen bond formation, although the molecular balance consideredi sr elativelyc omplexi nt erms of a large number of conformations it could potentially adopt. Furthermore, as previously emphasised, molecular balances with a relativelyl arge number of highly polar bonds are likely to display additional noncovalent interactions, whicha re difficult to account for fully,especially in solution.…”

Section: Other Balancesmentioning

confidence: 99%

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Some Recent Advances in the Design and Use of Molecular Balances for the Experimental Quantification of Intramolecular Noncovalent Interactions of π Systems

Aliev

Motherwell

2019

Chemistry A European J

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Herein, various molecular balances used for comparing the strengths of intramolecular noncovalent interactions are reviewed. Our overview indicates that considerable quantitative insight into the strength of noncovalent interactions can be gained through the careful design of molecular balances. Many exciting opportunities certainly exist for the design of further new balances to quantify and dissect the relative strengths of noncovalent interactions as a function of solvation and the importance of the many factors that contribute to overall molecular recognition. However, even simple model molecules can show a multiplicity of intramolecular noncovalent interactions acting in a combined fashion. It is therefore essential to undertake a detailed computational analysis to identify all possible noncovalent interactions present in a selected molecular balance prior to a quantitative experimental assessment of the strength of a particular noncovalent interaction. It is also argued that the words “torsion” and “molecular balance” seem to have become inextricably linked and, in consequence, even top pan and seesaw balances have been mistakenly referred to in these terms.

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“…The perturbation of the equilibrium by the interaction, typically measured by NMR, reflects the interaction’s strength. 14–18 Molecular balances have also been used to measure helical propensities of amino acids via template-induced helix initiation. 19 They can sensitively measure weak interactions and, because they are synthetic, the interacting functional groups can be varied to probe the nuances of the interaction in question.…”

Section: Introductionmentioning

confidence: 99%

Using Cooperatively Folded Peptides To Measure Interaction Energies and Conformational Propensities

Ardejani

Powers

2017

Acc. Chem. Res.

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Conspectus The rates and equilibria of the folding of biopolymers are determined by the conformational preferences of the subunits that make up the sequence of the biopolymer and by the interactions that are formed in the folded state. Because of the centrality of these processes to life, quantifying conformational propensities and interaction strengths is vitally important to understanding biology. In this Account, we describe our use of peptide model systems that fold cooperatively, yet are small enough to be chemically synthesized to measure such quantities. The necessary measurements are made by perturbing an interaction or conformation of interest by mutation and measuring the difference between the folding free energies of the wild type (in which the interaction or conformation is undisturbed) and the mutant model peptides (in which the interaction has been eliminated or the conformational propensities modified). With the proper controls, and provided that the peptide model system in question folds via a two-state process, these folding free energy differences can be accurate measures of interaction strengths or conformational propensities. This method has the advantage of having high sensitivity and high dynamic range because the energies of interest are coupled to folding free energies, which can be measured with precisions on the order of a few tenths of a kilocalorie by well-established biophysical methods, like chaotrope or thermal denaturation studies monitored by fluorescence or circular dichroism. In addition, because the model peptides can be chemically synthesized, the full arsenal of natural and unnatural amino acids can be used to tune perturbations to be as drastic or subtle as desired. This feature is particularly noteworthy because it enables the use of analytical tools developed for physical organic chemistry, especially linear free energy relationships, to decompose interaction energies into their component parts to obtain a deeper understanding of the forces that drive interactions in biopolymers. We have used this approach, primarily with the WW domain derived from the human Pin1 protein as our model system, to assess hydrogen bond strengths (especially those formed by backbone amides); the dependence of hydrogen bond strengths on the environment in which they form; β-turn propensities of both natural sequences and small molecule β-turn mimics; and the energetics of carbohydrate–protein interactions. In each case, the combination of synthetic accessibility, the ease of measuring folding energies, and the robustness of the structure of the Pin1 WW domain to mutation enabled us to obtain incisive measurements of quantities that have been challenging to measure by other methods.

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Synthesis and NMR Analysis of a Conformationally Controlled β-Turn Mimetic Torsion Balance

Cited by 10 publications

References 69 publications

Strong Short‐Range Cooperativity in Hydrogen‐Bond Chains

Strong Short‐Range Cooperativity in Hydrogen‐Bond Chains

Some Recent Advances in the Design and Use of Molecular Balances for the Experimental Quantification of Intramolecular Noncovalent Interactions of π Systems

Using Cooperatively Folded Peptides To Measure Interaction Energies and Conformational Propensities

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