Systematic Targeting of Protein–Protein Interactions

Modell, Ashley E.; Blosser, Sarah L.; Arora, Paramjit S.

doi:10.1016/j.tips.2016.05.008

Cited by 159 publications

(150 citation statements)

References 118 publications

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“…43 In terms of the recognition of open protein surfaces, supramolecular chemists have been inspired by protein-protein recognition sites and the recognition of convex protein surfaces. 109 Interestingly, examples such as barnase-barstar demonstrate the existence and role of water molecules at specific points in the protein-protein interface, i.e., it is not necessary to remove all interfacial waters for selective, tight recognition. 110 This is an important point for supramolecular chemists designing systems for protein recognition, and raises the question as to whether supramolecular systems can be designed to probe the effects of interfacial water.…”

Section: Recognition Mimicry and Interactions With Biomoleculesmentioning

confidence: 99%

Collaborative routes to clarifying the murky waters of aqueous supramolecular chemistry

et al. 2017

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Collaborative routes to clarifying the murky waters of aqueous supramolecular chemistry. AbstractOn planet Earth, water is everywhere: the majority of the surface is covered with it; it is a key component of all life; its vapor and droplets fill the lower atmosphere; even rocks contain it and undergo geomorphological changes because of it. A community of physical scientists largely drives studies of the chemistry of water and aqueous solutions, with expertise in biochemistry, spectroscopy, and computer modeling. More recently however, supramolecular chemistry -with its expertise in macrocyclic synthesis and measuring supramolecular interactions -have renewed their interest in water-mediated non-covalent interactions. These two groups offer complementary expertise that, if harnessed, offers to accelerate our understanding of aqueous supramolecular chemistry and water writ large. This review summarizes the state-of-the-art of the two fields, and highlights where there is latent chemical space for collaborative exploration by the two groups. 4Water is ubiquitous and essential to life on planet Earth. A full understanding of aqueous solutions is therefore of significance to a wide range of fields within the atmospheric, environmental, biological and geological sciences. Within the chemical sciences, a deeper appreciation of how non-covalent interactions and chemical transformations are influenced by water would benefit a variety of fields. However, as we highlight here, there are many open questions regarding the chemical and physical properties of aqueous solutions.The aqueous realm is frequently bifurcated into the Hofmeister and hydrophobic effects, phenomena that respectively deal with the properties of solutions of salts and relatively nonpolar molecules. However, it is becoming increasingly evident that these areas do in fact frequently overlap; two prime examples being the accumulation of large polarizable anions at the air-water interface, 1-5 and the favorable interactions of polarizable anions with non-polar surfaces. [6][7][8][9][10][11][12][13][14][15] Thus the hydrophobic and Hofmeister effects are but part of a greater continuum of aqueous supramolecular chemistry, with many important and outstanding questions regarding the influence of the different kinds of non-covalent interactions involved.Studies of water and aqueous solutions have mostly been driven by the physical sciences community, a broad range of scientists whose expertise in spectroscopy, computer modeling, and biochemistry (to name just three areas) has generally not involved macrocycles or host molecules in general. However, for some time now, supramolecular chemists -with their expertise in macrocyclic synthesis and measuring weak non-covalent interactions -have been travelling a parallel course of exploration. This Review, inspired by discussions between sixteen members of each community at a recent workshop, 16 is an attempt to summarize what we know about aqueous solutions, what we do not know about them, and where the two communit...

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Section: Recognition Mimicry and Interactions With Biomoleculesmentioning

confidence: 99%

Collaborative routes to clarifying the murky waters of aqueous supramolecular chemistry

et al. 2017

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“…1 Mimicry of protein secondary structures has led to the development of successful inhibitors of protein–protein interactions (PPIs). 2–7 To categorize complexes mediated by secondary structures and motivate subsequent design of interfacial peptidomimetics, we and others have analyzed entries in the Protein Data Bank (PDB) and cataloged high affinity secondary structure elements at interfaces. 8–11 These efforts used computational alanine scanning analysis to identify hot spot residues, residues whose mutation to alanine results in an estimated ΔΔ G of binding > 1 kcal/mol.…”

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confidence: 99%

Side-Chain Conformational Preferences Govern Protein–Protein Interactions

Watkins¹,

Bonneau

Arora³

2016

J. Am. Chem. Soc.

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Protein secondary structures serve as geometrically constrained scaffolds for the display of key interacting residues at protein interfaces. Given the critical role of secondary structures in protein folding and the dependence of folding propensities on backbone dihedrals, secondary structure is expected to influence the identity of residues that are important for complex formation. Counter to this expectation, we find that a narrow set of residues dominates the binding energy in protein–protein complexes independent of backbone conformation. This finding suggests that the binding epitope may instead be substantially influenced by the side-chain conformations adopted. We analyzed side-chain conformational preferences in residues that contribute significantly to binding. This analysis suggests that preferred rotamers contribute directly to specificity in protein complex formation and provides guidelines for peptidomimetic inhibitor design.

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“…These PPIs play a critical role in numerous biological processes and represent a rich array of potential therapeutic targets345. Despite small molecule’s therapeutic potential6789, development of small molecule PPI ligands is still formidable due to the shallow, large, and even disconnected PPI surfaces10; meanwhile, large proteins are often unsuitable for intracellular PPIs due to poor cell permeability.…”

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confidence: 99%

Chiral Sulfoxide-Induced Single Turn Peptide α-Helicity

Zhang

Jiang

et al. 2016

Sci Rep

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Inducing α-helicity through side-chain cross-linking is a strategy that has been pursued to improve peptide conformational rigidity and bio-availability. Here we describe the preparation of small peptides tethered to chiral sulfoxide-containing macrocyclic rings. Furthermore, a study of structure-activity relationships (SARs) disclosed properties with respect to ring size, sulfur position, oxidation state, and stereochemistry that show a propensity to induce α-helicity. Supporting data include circular dichroism spectroscopy (CD), NMR spectroscopy, and a single crystal X-ray structure for one such stabilized peptide. Finally, theoretical studies are presented to elucidate the effect of chiral sulfoxides in inducing backbone α-helicity.

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Systematic Targeting of Protein–Protein Interactions

Cited by 159 publications

References 118 publications

Collaborative routes to clarifying the murky waters of aqueous supramolecular chemistry

Collaborative routes to clarifying the murky waters of aqueous supramolecular chemistry

Side-Chain Conformational Preferences Govern Protein–Protein Interactions

Chiral Sulfoxide-Induced Single Turn Peptide α-Helicity

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