Elaborate Supramolecular Architectures Formed by Co-Assembly of Metal Species and Peptoid Macrocycles

Abstract

Peptoids are a family of sequence-specific oligomers capable of mimicking the structure and function of polypeptides. The innate folding and self-assembly capabilities of peptoid oligomers can be enhanced by the presence of coordinated metal ions. In this work, we explore the co-assembly of water-soluble hexameric and tetrameric peptoid macrocycles with Na + and K + ions. Solid-state structures were solved for six cyclopeptoid−metal coassemblies by X-ray diffraction using single crystals grown from fully aqueous solutions. Subtle variations in the peptoid oligomer composition give rise to dramatic alterations in the supramolecular assemblies. Some structures feature extensively hydrated porous architectures that include unusual metal ion clusters. The ability to study the metallopeptoid structure at an atomic resolution in crystals obtained from an aqueous solution is an important advancement, as most previous peptoid crystal structures were obtained from nonaqueous or cosolvent solutions. These results will facilitate the design of peptoids and other foldamers for the assembly of supramolecular frameworks.

Evaluating the Conformations and Dynamics of Peptoid Macrocycles

“…To develop an understanding of possible transition paths between the conformations identified in this study, we performed simulations of the conversion between two hexamer conformations: those with tttttt and ttcttc amide patterns. These two simulation results correspond to two conformations discovered co-occupying a position within the unit cell of a recently published crystal structure of Ncm6 . The previously published crystal structures were determined at 100 K; to gain more insight into the thermodynamic properties of these unique conformational features and confirm their relevance under ambient conditions, we redetermined the crystal structures of compound Ncm6 at 295 K in this work.…”

“…Due to these many subtle stereochemical features, the energy landscape of cyclic peptoid conformations is highly complex. As mentioned, experimental studies of cyclic peptoids have identified a number of distinct conformations in the solid phase, including two novel structures reported after the initiation of this work 23,24 and a third reported here. Voelz et al have previously demonstrated a method using the Generalized Amber Force Field (GAFF) in molecular dynamics (MD) simulations that reproduces experimental structures 26 and successfully predicted the conformation of a novel cyclic peptoid nonamer.…”

“…The transition pathway between the tttttt and cttctt hexamer backbones, as observed in the cited crystal structure, was simulated using the Swarm-of-Trajectories String Method as reported by Pan et al and implemented in Amber18 as part of the Adaptively-Biased Molecular Dynamics (ABMD) free energy methods suite. The exemplar structure corresponding to the all- trans -amide hexamer was used as the starting conformation.…”

“…These two simulation results correspond to two conformations discovered co-occupying a position within the unit cell of a recently published crystal structure of Ncm6. 24 The previously published crystal structures were determined at 100 K; to gain more insight into the thermodynamic properties of these unique conformational features and confirm their relevance under ambient conditions, we redetermined the crystal structures of compound Ncm6 at 295 K in this work. No difference was observed in terms of the conformations adopted by compound Ncm6 except the occupancy of the ttcttc conformer increased from 80% at 100 K to 84% at 295 K and the tttttt conformer decreased by the corresponding amount.…”

“…NMR studies of cyclic peptoids in solution, however, often reveal a conformational ensemble . X-ray crystallographic studies establish that, for a given macrocycle size, more than one of these conformations can be stabilized within the solid state, − with the structures appearing to depend on the side chain functional groups and additional influences from counterions. It is worth noting that all previously observed crystal structure conformations of cyclic peptoids with even numbers of residues (the preponderance of all cyclic peptoids crystallized) contain an element of two-fold rotational symmetry within each molecule.…”