Interaction and Dimerization Energies in Methyl-Blocked α,γ-Peptide Nanotube Segments

Abstract

The building blocks of a promising class of peptide nanotubes composed of alternating D-alpha-amino acids and (1R,3S)-3-aminocyclohexane (or cyclopentane) carboxylic acid (D-gamma-Ach or D-gamma-Acp) were explored by computational methods. Specifically, density functional theory (DFT) calculations on monomers and dimers of gamma-Ach-based and gamma-Acp-based alpha,gamma-cyclo-hexapeptides and cyclo-octapeptides were carried out to investigate the experimentally observed preference for alpha-alpha over gamma-gamma dimerization, associated with the two types of stacking patterns present in these peptide nanotubes, as well as the preference for heterodimerization versus homodimerization. Full geometry optimizations were performed at the B3LYP/6-31G(d) level, and single point calculations were subsequently carried out with the B3LYP and M05-2X functionals and the 6-31+G(d,p) basis set. The calculations predict that the interaction energies in the alpha-alpha species are quite similar to those in the gamma-gamma dimers. However, a comparison of dimerization energies (i.e., interaction energies plus deformation energies of monomers) shows that alpha-alpha dimerization is energetically favored over gamma-gamma dimerization. The calculations strongly suggest that the preference for alpha-alpha binding is governed by differences between the deformation energies in the alpha and gamma monomers, rather than by differences between the relative strengths of the alpha-alpha and gamma-gamma hydrogen-bonding patterns. Calculations based on local properties of the electron density support the previous suggestion that the H-N bonds of the alpha-amino acids are more polarized than those of the gamma-amino acids.

Highly Efficient and Directional Homo‐ and Heterodimeric Energy Transfer Materials Based on Fluorescently Derivatized α,γ‐Cyclic Octapeptides

“…In this case, as mentioned before, the excimer formation is only geometrically possible for the minor dimer (D 11c [E] ), a situation that made the measurement of its association constant more difficult and less accurate. Despite this, the association constant was estimated to be of a similar order, albeit slightly lower, than that for the Acp‐based CPs, K A (CHCl 3 )=1.2×10 8 M −1 (Figure SI‐7 in the Supporting Information), as predicted by our previous DFT calculations 11…”

“…Herein, we report a further extension of the selective heterodimer formation between cyclic α,γ‐octapeptides based on γ‐Ach residues with those containing γ‐Acp. In these systems the preferential heterodimer formation is, once again, driven by the backbone–backbone interactions, as well as by the entropy of mixing (Δ S mix ) 11. 14 Although the Δ S mix is expected to increase, the heterodimer formation should not alter significantly the overall trend in association constants.…”

Parallel Versus Antiparallel β‐Sheet Structure in Cyclic Peptide Hybrids Containing γ‐ or δ‐Cyclic Amino Acids

“…21.2 Å in the antiparallel arrangement. The inter‐peptide distances in the dimers (considering the CP skeleton), are about 5.1–5.2 Å, a bit longer than those calculated in CP dimers formed by α,γ‐CPs …”

Computational Approaches to Understanding the Self‐assembly of Peptide‐based Nanostructures

“…The optimisations were carried out at the M05-2X/6-31+G(d,p) level of theory [18] and the binding energies were corrected for basis set superposition error. In the gas phase, the parallel dimer was calculated as having a binding energy of -34.4 kcal/mol and the antiparallel dimer with a binding energy of -23.0 kcal/mol.…”