Salt‐Induced Adaptation of a Dynamic Combinatorial Library of Pseudopeptidic Macrocycles: Unraveling the Electrostatic Effects in Mixed Aqueous Media

Abstract

Dynamic combinatorial libraries are powerful systems for studying adaptive behaviors and relationships, as models of more complex molecular networks. With this aim, we set up a chemically diverse dynamic library of pseudopeptidic macrocycles containing amino-acid side chains with differently charged residues (negative, positive, and neutral). The responsive ability of this complex library upon the increase of the ionic strength has been thoroughly studied. The families of the macrocyclic members concentrating charges of the same sign showed a large increase in its proportion as the ionic strength increases, whereas those with residues of opposite charges showed the reverse behavior. This observation suggested an electrostatic shielding effect of the salt within the library of macrocycles. The top-down deconvolution of the library allowed us to obtain the fundamental thermodynamic information connecting the library members (exchange equilibrium constants), as well as to parameterize the adaptation to the external stimulus. We also visualized the physicochemical driving forces for the process by structural analysis using NMR spectroscopy and molecular modeling. This knowledge permitted the full understanding of the whole dynamic library and also the de novo design of dynamic chemical systems with tailored co-adaptive relationships, containing competing or cooperating species. This study highlights the utility of dynamic combinatorial libraries in the emerging field of systems chemistry.

Non‐covalent Interactions for the Preparation of Pseudopeptidic Synthetic Compounds and Materials

“…Following this study, a more diverse and complex library was prepared containing positive, negative, and neutral residues within the same backbone pseudopeptide [44]. Following this study, a more diverse and complex library was prepared containing positive, negative, and neutral residues within the same backbone pseudopeptide [44].…”

Unraveling the Multistimuli Responses of a Complex Dynamic System of Pseudopeptidic Macrocycles

“…Within our research interest in constitutional dynamic chemistry, we have recently described a DCL of macrocyclic pseudopeptides able to respond to a meaningful biological stimulus: the increase of the salt concentration . During that study and for a suitable description of the system as a whole, we carried out the corresponding dynamic deconvolution up to the minimal sub‐libraries able to adapt to the same trigger.…”

“…To achieve that, three different stimuli were applied. The first one is the ionic strength, which had been thermodynamically characterized by us for the same library . This allows comparing the conclusions extracted from the two alternative approaches.…”

Selective Dynamic Assembly of Disulfide Macrocyclic Helical Foldamers with Remote Communication of Handedness

“…[4] Extensions of this concept include various stapling methods between amino acid side chains with chemical functions other than disulfides. [7,8] Thef ormation of aparticular macrocycle then reflects its intrinsic stability and the preorganization of the dithiol precursor for cyclization. [6] In proteins,e xchange reactions are critical to correct mismatched bridges when more than two cysteine residues are available.T hiol-disulfide exchange has also emerged as ap owerful method for the dynamic covalent assembly of macrocycles from several dithiol units.…”