Experimental and Computational Models for Side Chain Discrimination in Peptide–Protein Interactions

Abstract

A bis(18-crown-6) Tröger's base receptor and 4substituted hepta-1,7-diyl bisammonium salt ligands have been used as a model system to study the interactions between non-polar side chains of peptides and an aromatic cavity of a protein. NMR titrations and NOESY/ROESY NMR spectroscopy were used to analyze the discrimination of the ligands by the receptor based on the substituent of the ligand, both quantitatively (free binding energies) and qualitatively (conformations). The analysis showed that an allanti conformation of the heptane chain was preferred for most of the ligands, both free and when bound to the receptor, and that for all of the receptor-ligand complexes, the substituent was located inside or partly inside of the aromatic cavity of the receptor. We estimated the free binding energy of a methyl-and a phenyl group to an aromatic cavity, via CH-π, and combined aromatic CH-π and π-π interactions to be À 1.7 and À 3.3 kJ mol À 1 , respectively. The experimental results were used to assess the accuracy of different computational methods, including molecular mechanics (MM) and density functional theory (DFT) methods, showing that MM was superior. Results and Discussion Description of the model systemReceptor 1 consists of a Tröger's base motif with 18-crown-6 moieties fused to each end of the aromatic cavity, and is synthesized in one step by the condensation of commercially [a] A

The Last Fortress of Tin's Tyranny – Protodenitration of Nitroalkanes

“… Applications of the Ono‐Tanner reaction between 2019 and 2021 by Wang and Guo (2019), [213] Yuan (2019), [214] Yuan (2019), [215] Valeev (2020), [216] Seidel (2020), [217] Cobb (2020), [218] Wang and Guo (2020), [219] Zhang (2020), [220] Pan (2021), [221] Norrby and Wärnmark (2021), [222] Matsuo (2021), [223] and Corey (2021) [224] …”

“…Thus, the replacement of Bu 3 SnH became an important goal in the field, and multiple options emerged over the past four decades. Traditional reducing 2019), [213] Yuan (2019), [214] Yuan (2019), [215] Valeev (2020), [216] Seidel (2020), [217] Cobb (2020), [218] Wang and Guo (2020), [219] Zhang (2020), [220] Pan (2021), [221] Norrby and Wärnmark (2021), [222] Matsuo (2021), [223] and Corey (2021). [224] Scheme 11.…”

Counterintuitive Electrostatics upon Metal Ion Coordination to a Receptor with Two Homotopic Binding Sites

“…While the majority of the studies of CE-based synthetic receptors concern receptors containing a single CE, we herein present a study of the thermodynamics governing the binding of potassium ions to a ditopic bis­(18-crown-6) analogue of Tröger’s base (BCETB, Figure ). , The association of multiple cations to a single, multitopic receptor represents an interesting thermodynamic system, with many different factors contributing to the overall stability of the complex. Previous studies of host–guest complexes containing two metal cations have employed interaction models including cation–cation repulsion and solvation effects to explain experimental observations. − Overall, considering also the interactions within the complex, the absolute binding affinity of the cation relies on a balance between the desolvation of the ion and the binding site and the subsequent formation of intermolecular interactions when the ion is fixed in the binding site, involving both interactions within the complex and interactions between the complex and the solvent.…”

“…12−14 While the majority of the studies of CE-based synthetic receptors concern receptors containing a single CE, we herein present a study of the thermodynamics governing the binding of potassium ions to a ditopic bis (18-crown-6) analogue of Troger's base (BCETB, Figure 1). 15,16 The association of multiple cations to a single, multitopic receptor represents an interesting thermodynamic system, with many different factors contributing to the overall stability of the complex. Previous studies of host−guest complexes containing two metal cations have employed interaction models including cation−cation repulsion and solvation effects to explain experimental observations.…”