Evaluating the Conformations and Dynamics of Peptoid Macrocycles

Abstract

Peptoid macrocycles are versatile and chemically diverse peptidomimetic oligomers. However, the conformations and dynamics of these macrocycles have not been evaluated comprehensively and require extensive further investigation. Recent studies indicate that two degrees of freedom, and four distinct conformations, adequately describe the behavior of each monomer backbone unit in most peptoid oligomers. On the basis of this insight, we conducted molecular dynamics simulations of model macrocycles using an exhaustive set of idealized possible starting conformations. Simulations of various sizes of peptoid macrocycles yielded a limited set of populated conformations. In addition to reproducing all relevant experimentally determined conformations, the simulations accurately predicted a cyclo-octamer conformation for which we now present the first experimental observation. Sets of three adjacent dihedral angles (ϕ i , ψi, ω i+1) exhibited correlated crankshaft motions over the course of simulation for peptoid macrocycles of six residues and larger. These correlated motions may occur in the form of an inversion of one amide bond and the concerted rotation of the preceding ϕ and ψ angles to their mirror-image conformation, a variation on “crankshaft flip” motions studied in polymers and peptides. The energy landscape of these peptoid macrocycles can be described as a network of conformations interconnected by transformations of individual crankshaft flips. For macrocycles of up to eight residues, our mapping of the landscape is essentially complete.

Guidelines for designing peptoid structures: Insights from the Peptoid Data Bank

“…Nevertheless, peptoid crystal structures have proved to be a valuable data set for understanding conformational preferences, and QM and MM studies have been correlated with these results. [43][44][45]…”

A Model for the Rapid Assessment of Solution Structures for 24-Atom Macrocycles: The Impact of β-Branched Amino Acids on Conformation

“…This belief allows molecular parameters to be rationally fine-tuned across a bounded chemical space vis-à-vis the exploration of aliphatic groups to promote hydrophobic interactions. However, this assumption appears increasingly tenuous for macrocycles that contort between multiple conformations of similar energy. − As a result, slight changes to the composition can change the distribution of conformations as well as offer access to new conformation space. − Understanding and ultimately engineering conformation are of great interest as the community pursues the development of macrocyclic drugs. − …”

Water-Soluble Chiral Cyclic Peptoids and Their Sodium and Gadolinium Complexes: Study of Conformational and Relaxometric Properties

“…Efforts to control their conformation have been plagued by the weak intramolecular hydrogen bond network and fast cis / trans tertiary amide interconversion . However, covalent constraints induced by head-to-tail cyclization, metal chelation, − and stereoelectronic effects between side chains and the backbone play a significant role in rigidifying their structure. ,, Interestingly, in contrast with linear congeners, − few contributions report structural studies dealing with water-soluble cyclic peptoids . To fill this gap, we embarked on the synthesis of the first chiral, water-soluble, cyclic tetra-, hexa-, and octamer peptoids incorporating N -( S )- and N -( R )-(1-carboxyethyl)­glycine monomers ( N sce and N rce, respectively), also mixed with sarcosine, and explored their general conformational properties as sodium salts.…”