Hierarchical Self-Assembly Pathways of Peptoid Helices and Sheets

Abstract

Peptoids (N-substituted glycines) are a class of tailorable synthetic peptidomic polymers. Amphiphilic diblock peptoids have been engineered to assemble 2D crystalline lattices with applications in catalysis and molecular separations. Assembly is induced in an organic solvent/water mixture by evaporating the organic phase, but the assembly pathways remain uncharacterized. We conduct all-atom molecular dynamics simulations of Nbrpe6Nc6 as a prototypical amphiphilic diblock peptoid comprising an NH2-capped block of six hydrophobic N-((4-bromophenyl)­ethyl)­glycine residues conjugated to a polar NH3(CH2)5CO tail. We identify a thermodynamically controlled assembly mechanism by which monomers assemble into disordered aggregates that self-order into 1D chiral helical rods then 2D achiral crystalline sheets. We support our computational predictions with experimental observations of 1D rods using small-angle X-ray scattering, circular dichroism, and atomic force microscopy and 2D crystalline sheets using X-ray diffraction and atomic force microscopy. This work establishes a new understanding of hierarchical peptoid assembly and principles for the design of peptoid-based nanomaterials.

Computational and Experimental Determination of the Properties, Structure, and Stability of Peptoid Nanosheets and Nanotubes

“…This result suggests that it may be equally easy to bend a parallel V Nbrpm6Nc6 nanosheet in x and y , such that we might anticipate these nanotubes to be a mixture of these geometries. However, previous calculations have identified the parallel V and antiparallel V morphologies to be equally thermodynamically stable, suggesting that nanosheets may comprise a mixture of these two structures . It is anticipated that the much larger Y y value for the antiparallel V components of the sheet would resist bending in y and make bending in x net more favorable overall.…”

“…Peptoid sequences are constructed using Avogadro 1.2.0 and modeled using the improved all-atom CGenFF peptoid force field developed by Weiser and Santiso as a peptoid-tuned modification of the CHARMM22 peptide force field. − We observe that alternative choices of force field exist, including the MFTOID model and the DREIDING-based PEPDROID model . Experimentally, peptoid assembly typically proceeds by dissolution in an organic solvent/water mixture and then slowly evaporating the organic phase to induce hydrophobic association into the terminal nanoaggregates that are the thermodynamically stable state in the final pure water solvent. ,,− We have previously explored the mechanistic pathways for the self-assembly of crystalline peptoid sheets as a function of solvent quality, but in this work we model only the terminal self-assembled nanoaggregates in a pure water environment. The amine group at the end of the Nc6 alkyl chain is assumed to be fully protonated as prefix− NH 3 + within the water solvent at pH 7.…”

“…To relax the initial configuration of the planar nanosheets, we employed a multistage equilibration protocol in the semi-isotropic NPT ensemble. 41 We heated the systems from 0 to 300 K in increments of 50 K over the course of 30 ps using a velocity rescaling thermostat 58 with a time constant of 0.1 ps and maintained the pressure at 1 bar using a Berendsen barostat 59 with a time constant of 1.0 ps and a compressibility of 4.5 × 10 −5 bar −1 for the independently coupled xy and z dimensions. We then performed relaxation runs of 1 μs in the semi-isotropic NPT ensemble at 300 K and 1 bar employing a Nose−Hoover thermostat 60 with a time constant of 1.0 ps and a Parrinello−Rahman barostat 61 with a time constant of 1.0 ps and compressibility of 4.5 × 10 −5 bar −1 for the xy and z dimensions.…”

Computational design of self-assembling peptide chassis materials for synthetic cells

“…We also note that the chain in bulk solvent is still harmonically restrained in the z-dimension and we can analytically estimate the free energy change associated with the release of these constraints and the COM translational entropy gain associated with the chain exploring the free volume accessible to it at a standard concentration of 1 mol L −1 . [62][63][64] To do this, we assume an effective harmonic constraint on z COM , the z-component of the displacement from the COM of bilayer to the COM of the entire pulled chain, when the pulled chain exists in bulk solvent. We estimate the spring constant K r of the effective harmonic restraint by collecting histograms of z COM from the equilibrated portions of all umbrella sampling windows within bulk solvent, fit Gaussian distributions to each of these histograms, estimate the spring constants from the standard deviations of a Gaussian fit, and take the mean as our estimate of K r .…”

Atomic-Scale Corrugations in Crystalline Polypeptoid Nanosheets Revealed by Three-Dimensional Cryogenic Electron Microscopy

“…While the XRD measurements have been frequently used to investigate the internal ordered structure of nanosheets by comparing the fingerprint peaks with atomic models generated by DFT or MD simulations, the assignments of some structural features are still under debate. − , To directly reveal the structural information, which is buried in the direction parallel with the incident electron beam in the nanosheet, images must be collected from tilted nanosheets and merged to reconstruct the 3D density map of the crystal lattice.…”