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A rotamer library to enable modeling and design of peptoid foldamers.

Renfrew PD, Craven TW, Butterfoss GL, Kirshenbaum K, Bonneau R - J. Am. Chem. Soc. (2014)

Bottom Line: We introduce a computational approach to provide accurate conformational and energetic parameters for peptoid side chains needed for successful modeling and design.We show by comparison to experimental peptoid structures that both methods provide an accurate prediction of peptoid side chain placements in folded peptoid oligomers and at protein interfaces.We have incorporated our peptoid rotamer libraries into ROSETTA, a molecular design package previously validated in the context of protein design and structure prediction.

View Article: PubMed Central - PubMed

Affiliation: Center for Genomics and Systems Biology, Department of Biology, ‡Department of Chemistry, and §Courant Institute of Mathematical Sciences, Computer Science Department, New York University , New York, New York 10003, United States.

ABSTRACT
Peptoids are a family of synthetic oligomers composed of N-substituted glycine units. Along with other "foldamer" systems, peptoid oligomer sequences can be predictably designed to form a variety of stable secondary structures. It is not yet evident if foldamer design can be extended to reliably create tertiary structure features that mimic more complex biomolecular folds and functions. Computational modeling and prediction of peptoid conformations will likely play a critical role in enabling complex biomimetic designs. We introduce a computational approach to provide accurate conformational and energetic parameters for peptoid side chains needed for successful modeling and design. We find that peptoids can be described by a "rotamer" treatment, similar to that established for proteins, in which the peptoid side chains display rotational isomerism to populate discrete regions of the conformational landscape. Because of the insufficient number of solved peptoid structures, we have calculated the relative energies of side-chain conformational states to provide a backbone-dependent (BBD) rotamer library for a set of 54 different peptoid side chains. We evaluated two rotamer library development methods that employ quantum mechanics (QM) and/or molecular mechanics (MM) energy calculations to identify side-chain rotamers. We show by comparison to experimental peptoid structures that both methods provide an accurate prediction of peptoid side chain placements in folded peptoid oligomers and at protein interfaces. We have incorporated our peptoid rotamer libraries into ROSETTA, a molecular design package previously validated in the context of protein design and structure prediction.

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Rotamer library coverageplot for Nphe, Ns1ne, Nmeo, and Nspepeptoid side chains. Interpolated χ torsions and standard deviationsof the closest rotamer in the rotamer library based on the backbonedihedral angles of each experimental point are shown as crosses, wherethe center of the cross is at the mean and the length represents ±1standard deviation. Rotamers for the k-means clustering (KMC) methodare shown as red crosses and quantum mechanically seeded (QMS) methodare shown in blue. Experimental χ1 and χ2 values are shown as black circles.
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fig4: Rotamer library coverageplot for Nphe, Ns1ne, Nmeo, and Nspepeptoid side chains. Interpolated χ torsions and standard deviationsof the closest rotamer in the rotamer library based on the backbonedihedral angles of each experimental point are shown as crosses, wherethe center of the cross is at the mean and the length represents ±1standard deviation. Rotamers for the k-means clustering (KMC) methodare shown as red crosses and quantum mechanically seeded (QMS) methodare shown in blue. Experimental χ1 and χ2 values are shown as black circles.

Mentions: To testthe completeness of the rotamer libraries produced by the KMC andQMS rotamer library creation protocols, we carried out rotamer library“coverage” tests. These tests calculate the RMSD (indegrees) between the experimentally observed side-chain rotamer conformationand the closest rotamer in the given rotamer library. Results of therotamer library coverage tests for the four frequently observed sidechains are shown in Figure 4 and Table 1. Results of the other experimental side chainsare shown in Figures S10–S14 and TableS5. For comparison, these tests were additionally carried outfor phenylalanine and methionine side chains in protein structuresin the Top 8000 data set52 using the Dunbrack2002 BBD rotamer library, Tables 1 and S7.


A rotamer library to enable modeling and design of peptoid foldamers.

Renfrew PD, Craven TW, Butterfoss GL, Kirshenbaum K, Bonneau R - J. Am. Chem. Soc. (2014)

Rotamer library coverageplot for Nphe, Ns1ne, Nmeo, and Nspepeptoid side chains. Interpolated χ torsions and standard deviationsof the closest rotamer in the rotamer library based on the backbonedihedral angles of each experimental point are shown as crosses, wherethe center of the cross is at the mean and the length represents ±1standard deviation. Rotamers for the k-means clustering (KMC) methodare shown as red crosses and quantum mechanically seeded (QMS) methodare shown in blue. Experimental χ1 and χ2 values are shown as black circles.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4227732&req=5

fig4: Rotamer library coverageplot for Nphe, Ns1ne, Nmeo, and Nspepeptoid side chains. Interpolated χ torsions and standard deviationsof the closest rotamer in the rotamer library based on the backbonedihedral angles of each experimental point are shown as crosses, wherethe center of the cross is at the mean and the length represents ±1standard deviation. Rotamers for the k-means clustering (KMC) methodare shown as red crosses and quantum mechanically seeded (QMS) methodare shown in blue. Experimental χ1 and χ2 values are shown as black circles.
Mentions: To testthe completeness of the rotamer libraries produced by the KMC andQMS rotamer library creation protocols, we carried out rotamer library“coverage” tests. These tests calculate the RMSD (indegrees) between the experimentally observed side-chain rotamer conformationand the closest rotamer in the given rotamer library. Results of therotamer library coverage tests for the four frequently observed sidechains are shown in Figure 4 and Table 1. Results of the other experimental side chainsare shown in Figures S10–S14 and TableS5. For comparison, these tests were additionally carried outfor phenylalanine and methionine side chains in protein structuresin the Top 8000 data set52 using the Dunbrack2002 BBD rotamer library, Tables 1 and S7.

Bottom Line: We introduce a computational approach to provide accurate conformational and energetic parameters for peptoid side chains needed for successful modeling and design.We show by comparison to experimental peptoid structures that both methods provide an accurate prediction of peptoid side chain placements in folded peptoid oligomers and at protein interfaces.We have incorporated our peptoid rotamer libraries into ROSETTA, a molecular design package previously validated in the context of protein design and structure prediction.

View Article: PubMed Central - PubMed

Affiliation: Center for Genomics and Systems Biology, Department of Biology, ‡Department of Chemistry, and §Courant Institute of Mathematical Sciences, Computer Science Department, New York University , New York, New York 10003, United States.

ABSTRACT
Peptoids are a family of synthetic oligomers composed of N-substituted glycine units. Along with other "foldamer" systems, peptoid oligomer sequences can be predictably designed to form a variety of stable secondary structures. It is not yet evident if foldamer design can be extended to reliably create tertiary structure features that mimic more complex biomolecular folds and functions. Computational modeling and prediction of peptoid conformations will likely play a critical role in enabling complex biomimetic designs. We introduce a computational approach to provide accurate conformational and energetic parameters for peptoid side chains needed for successful modeling and design. We find that peptoids can be described by a "rotamer" treatment, similar to that established for proteins, in which the peptoid side chains display rotational isomerism to populate discrete regions of the conformational landscape. Because of the insufficient number of solved peptoid structures, we have calculated the relative energies of side-chain conformational states to provide a backbone-dependent (BBD) rotamer library for a set of 54 different peptoid side chains. We evaluated two rotamer library development methods that employ quantum mechanics (QM) and/or molecular mechanics (MM) energy calculations to identify side-chain rotamers. We show by comparison to experimental peptoid structures that both methods provide an accurate prediction of peptoid side chain placements in folded peptoid oligomers and at protein interfaces. We have incorporated our peptoid rotamer libraries into ROSETTA, a molecular design package previously validated in the context of protein design and structure prediction.

Show MeSH
Related in: MedlinePlus