Insights into Peptoid Helix Folding Cooperativity from an Improved Backbone Potential

Mukherjee, Sudipto; Zhou, Guangfeng; Michel, Chris; Voelz, Vincent A.

doi:10.1021/acs.jpcb.5b09625

Cited by 43 publications

(73 citation statements)

References 80 publications

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“…On the other hand, the ÀTDS P conf between the b II 0 þb II 0 and b II þb II conformations shows that the b II 0 þb II 0 conformation was relatively favorable in configurational entropy. Peptide entropy plays an important role in protein folding, peptoid helix formation, and dimerization (43)(44)(45). In protein folding, FIGURE 5 1 H NMR spectra for P7, P6, and P7 analogs V1I, V1T, V1S, and V1L.…”

Section: Resultsmentioning

confidence: 99%

β-Branched Amino Acids Stabilize Specific Conformations of Cyclic Hexapeptides

Cummings

Miao

Slough

et al. 2019

Biophysical Journal

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Cyclic peptides (CPs) are a promising class of molecules for drug development, particularly as inhibitors of protein-protein interactions. Predicting low-energy structures and global structural ensembles of individual CPs is critical for the design of bioactive molecules, but these are challenging to predict and difficult to verify experimentally. In our previous work, we used explicit-solvent molecular dynamics simulations with enhanced sampling methods to predict the global structural ensembles of cyclic hexapeptides containing different permutations of glycine, alanine, and valine. One peptide, cyclo-(VVGGVG) or P7, was predicted to be unusually well structured. In this work, we synthesized P7, along with a less well-structured control peptide, cyclo-(VVGVGG) or P6, and characterized their global structural ensembles in water using NMR spectroscopy. The NMR data revealed a structural ensemble similar to the prediction for P7 and showed that P6 was indeed much less well-structured than P7. We then simulated and experimentally characterized the global structural ensembles of several P7 analogs and discovered that b-branching at one critical position within P7 is important for overall structural stability. The simulations allowed deconvolution of thermodynamic factors that underlie this structural stabilization. Overall, the excellent correlation between simulation and experimental data indicates that our simulation platform will be a promising approach for designing well-structured CPs and also for understanding the complex interactions that control the conformations of constrained peptides and other macrocycles.

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Section: Resultsmentioning

confidence: 99%

β-Branched Amino Acids Stabilize Specific Conformations of Cyclic Hexapeptides

Cummings

Miao

Slough

et al. 2019

Biophysical Journal

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“…36 Importantly, this method of sterically inducing the helical conformation is remarkably stable across a range of solvents and temperatures in solution and may form entropically stabilized helices (unlike hydrogen-bond-stabilized helices, which transition to an unstructured state above a critical temperature). 34,43 This remarkably environment-independent and stable helix makes it ideal for bulk studies. Indeed, circular dichroism measurements of this polypeptoid in a solid-state thin film shows that the ellipticity signal observed in solution is maintained in the solidstate (Supporting Information Figure 3).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Impact of Helical Chain Shape in Sequence-Defined Polymers on Polypeptoid Block Copolymer Self-Assembly

et al. 2018

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Controlling the self-assembly of block copolymers with variable chain shape and stiffness is important for driving the self-assembly of functional materials containing nonideal chains as well as for developing materials with new mesostructures and unique thermodynamic interactions. The polymer helix is a particularly important functional motif. In the helical chain, the traditional scaling relationships between local chain stiffness and space-filling properties are not applicable; this in turn impacts the scaling relationships critical for governing self-assembly. Polypeptoids, a class of sequence-defined peptidomimetic polymers with controlled helical secondary structure, were used to systematically investigate the impact of helical chain shape on block copolymer self-assembly in a series of poly(n-butyl acrylate)-b-polypeptoid block copolymers. Small-angle X-ray scattering (SAXS) of the bulk materials shows that block copolymers form hexagonally packed cylinder domains. By leveraging sequence control, the polypeptoid block was controlled to form a helix only at the part either adjacent to or distant from the block junction. Differences in domain size from SAXS reveal that chain stretching of the helix near the block junction is disfavored, while helical segments at the center of cylindrical domains contribute to unfavorable packing interactions, increasing domain size. Finally, temperature-dependent SAXS shows that helix-containing diblock copolymers disorder at lower temperatures than the equivalent unstructured diblock copolymers; we attribute this to the smaller effective N of the helical structure resulting in a larger entropic gain upon disordering. These results emphasize how current descriptions of rod/coil interactions and conformational asymmetry for coil polymers do not adequately address the behavior of chain secondary structures, where the scalings of space-filling and stiff−elastic properties relative to chain stiffness deviate from those of typical coil, semiflexible, and rodlike polymers.

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“…One of the earliest reported secondary structures for peptoids is the peptoid helix . In the peptoid helix, the N ‐alkylation of peptoids prevents any intramolecular hydrogen bonding along the oligomer backbone, thus the helix is stabilized by intra‐residue and inter‐residue contacts and amide interactions . The cis backbone conformation creates a rather tight helical pitch (∼3 residues per turn) and allows the i and i + 3 peptoid side chains to potentially interact along one face of the helix.…”

Section: Assigning Peptoid Specific Regions To the Ramachandran Plotmentioning

confidence: 99%

Stereochemistry of polypeptoid chain configurations

et al. 2019

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Like polypeptides, peptoids, or N‐substituted glycine oligomers, have intrinsic conformational preferences due to their amide backbones and close spacing of side chain substituents. However, the conformations that peptoids adopt are distinct from polypeptides due to several structural differences: the peptoid backbone is composed of tertiary amide bonds that have trans and cis conformers similar in energy, they lack a backbone hydrogen bond donor, and have an N‐substituent. To better understand how these differences manifest in actual peptoid structures, we analyzed 46 high quality, experimentally determined peptoid structures reported in the literature to extract their backbone conformational preferences. One hundred thirty‐two monomer dihedral angle pairs were compared to the calculated energy landscape for the peptoid Ramachandran plot, and were found to fall within the expected minima. Interestingly, only two regions of the backbone dihedral angles ϕ and ψ were found to be populated that are mirror images of each other. Furthermore, these two conformers are present in both cis and trans forms. Thus, there are four primary conformers that are sufficient to describe almost all known backbone conformations for peptoid oligomers, despite conformational constraints imposed by a variety of side chains, macrocyclization, or crystal packing forces. Because these conformers are predominant in peptoid structure, and are distinct from those found in protein secondary structures, we propose a simple naming system to aid in the description and classification of peptoid structure.

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Insights into Peptoid Helix Folding Cooperativity from an Improved Backbone Potential

Cited by 43 publications

References 80 publications

β-Branched Amino Acids Stabilize Specific Conformations of Cyclic Hexapeptides

β-Branched Amino Acids Stabilize Specific Conformations of Cyclic Hexapeptides

Impact of Helical Chain Shape in Sequence-Defined Polymers on Polypeptoid Block Copolymer Self-Assembly

Stereochemistry of polypeptoid chain configurations

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