A rotamer library to enable modeling and design of peptoid foldamers

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.

Scheme 1. Four of the Most Common Side Chains in Peptoid Structures

Scheme 2. Side Chain and Backbone Atom and Torsion Naming for (S)-N-(1-Phenethyl)-glycine (Nspe)

Atom names shown as red italics in torsion angle definitions are atoms in the preceding (ω) or following (ψ) residues in a oligo-peptoid chain and not shown in scheme.

Scheme 3. Tertiary Amide Bond (TAB) Model, Torsion Angle, and Dunitz Parameter Definitions

Atoms are named as in Scheme 2, and names shown as green italics represent atoms from preceding residues in a oligo-peptoid chain.

Scheme 4. Backbone-Independent (BBI) (left) and Backbone-Dependent (BBD) “dipeptoid” (right) Models Used in the Rotamer Library Creation Protocols

Figure 1

Workflow for the k-means clustering (KMC) and quantum mechanically seeded (QMS) rotamer library construction protocols. Boxes shaded in green are QM geometry optimizations of backbone-dependent (BBD) or backbone-independent (BBI) models; red, inputs to ROSETTA; blue, geometry optimization using the ROSETTA mm_std energy function; yellow, identification of local energy minima. A more detailed explanation can be found in the main text.

Figure 2

Effects of the ω dihedral angle on the χ₁ energy landscape. Energy landscapes were generated by fixing the dihedral angles of the TAB model to simultaneously achieve the desired χ₁ or ω. Cis-ω angles can be found on the left, trans-ω can be found at the right. Crystal structure data are shown as circles and crosses for angles and parameters found in cyclic and linear peptoid structures, respectively. In the trans-ω energy landscapes, crystal structure values for the “Nary” monomer are not plotted, as this parameter does not match the chemistry of the TAB model system. The minimum energy parameters are plotted across the full range of ω values as well as for positive (solid line) and negative (dashed line) χ₁ values. All molecules were minimized and energies evaluated at the B3LYP/6-311+G(d,p) level of theory, and heatmaps generated using the lowest energy for each plot as the zero kcal/mol baseline.

Figure 3

Fixed backbone rotamer energy landscapes for Nphe, Nspe, Ns1ne, and N-(propyl)-glycine side chains in a backbone-independent (BBI) and backbone-dependent (BBD) context. Crystal structure dihedral angle values are shown as circles and crosses for those observed in cyclic and linear peptoid structures, respectively. X-ray crystal dihedral angles for the different side chains are plotted only for the monomers in which the backbone dihedral angles were observed to be within 20° of the fixed backbone dihedral angles used in the energy landscape calculations. The minima from the BBI model landscapes (Figure S9) are represented as large diamonds in the BBI portion of the figure on the left. The diamonds on the right portion of the figure represent these rotamer positions in the context of the BBD model after ROSETTA mm_std energy function minimization. All landscapes underneath a QM header had energies evaluated at the B3LYP/6-311+G(d,p) level of theory. Landscapes under a ROSETTA header had energies evaluated using the mm_std energy function. Heatmaps were generated using the lowest energy as each plot’s zero kcal/mol and zero REU (ROSETTA Energy Units) baseline for QM and ROSETTA, respectively.

Figure 4

Rotamer library coverage plot for Nphe, Ns1ne, Nmeo, and Nspe peptoid side chains. Interpolated χ torsions and standard deviations of the closest rotamer in the rotamer library based on the backbone dihedral angles of each experimental point are shown as crosses, where the center of the cross is at the mean and the length represents ±1 standard deviation. Rotamers for the k-means clustering (KMC) method are shown as red crosses and quantum mechanically seeded (QMS) method are shown in blue. Experimental χ₁ and χ₂ values are shown as black circles.

Figure 5

Peptoid data bank structure 12AC1-9-C and side-chain conformations after being repacked with (A) KMC rotamer libraries or (B) the QMS rotamer libraries. Experimental side-chain conformations are shown in gray, repacked side chains in blue, and repacked in the context of the symmetry related crystal partners in red. Positions for which the same rotamer was chosen in both contexts are shown in purple.