Molecular Dynamics Study of Nitrogen-Pyramidalized Bicyclic β-Proline Oligomers: Length-Dependent Convergence to Organized Structures

Abstract

In this study, the solution structures of the homooligomers of a conformationally constrained bicyclic proline-type β-amino acid were studied by means of molecular dynamics (MD) calculations in explicit methanol and water using the umbrella sampling method. The ratio of trans-amide and cis-amide was estimated by NMR and the rotational barrier of the amide of acetylated bicyclic amino acid monomer was estimated by two-dimensional (2D) exchange spectroscopy (EXSY) or line-shape analysis. A bias potential was introduced with respect to the amide torsion angle ω to enhance conformational exchange including isomerization of amide bonds by lowering the rotation energy barrier. After determination of reweighting parameters to best reproduce the experimental results of the monomer amide, the free energy profile around the amide torsion angle ω was obtained from the MD trajectory by reweighting of the biased probability density. The MD simulation results support the existence of invertomers of nitrogen-pyramidalized amide. Furthermore, extended structures with a high fraction of trans-amide conformation appear to be increasingly stabilized as the oligomer is elongated, both in methanol and in water. Our conformational analysis of natural and non-natural tertiary-amide-based peptide oligomers indicates that these oligomers preferentially adopt a limited number of conformations.

Theoretical and NMR Conformational Studies of β-Proline Oligopeptides With Alternating Chirality of Pyrrolidine Units

“…This is in good agreement with the value of approximately 19 kcal·mol −1 calculated from the analysis of the 1 H line shapes of tetramer 1 tert -butyl signals in NMR spectra recorded in the temperature range between 298 and 408 K (Supplementary Figure 5 ). This value is also in good aggreement with ΔG measured for Z↔E transition in acetyl-L-proline-NHMe (20.4 kcal·mol −1 ) (Doshi and Hamelberg, 2009 ), acetyl-L-proline-OMe (21.1 kcal·mol −1 ) (Renner et al, 2001 ) and in nitrogen-pyramidalized bicyclic β-proline oligomers (17.8 kcal·mol −1 ) (Otani et al, 2017 ).…”

“…Several attempts to achieve certain conformational control by substitution or bridging of pyrrolidine rings in the β-polyproline scaffold were reported (Otani et al, 2006 ; Krow et al, 2010 ; Wang et al, 2014 ). Circular dichroism (CD) (Huck et al, 1999 ; Kim et al, 2000 ; Caumes et al, 2013 ), X-ray crystallography (Krow et al, 2010 ; Kudryavtsev et al, 2013 , 2015a ; Wang et al, 2014 ), NMR spectroscopy (Huck et al, 2003 ; Krow et al, 2010 ; Caumes et al, 2013 ; Wang et al, 2014 ; Kudryavtsev et al, 2015a , b ) and quantum mechanics calculation (Otani et al, 2006 , 2017 ; Wang et al, 2014 ) revealed the formation of ordered structures in solution and solid state for the reported β-proline oligopeptides and indicated the presence of an equilibrium between several dominant conformations in solution.…”

Amide nitrogen pyramidalization changes lactam amide spinning

“…3b, Table 2, Supplementary Figs. 8–13) 39,40 . The free energies of rotation (∆ G t → c ‡ and ∆ G c → t ‡ ) were obtained from the enthalpy of activation (∆ H ‡ ) and the entropy of activation (∆ S ‡ ), which were derived from the slope and intercept of the Eyring plot of the rate against temperature (Table 2).…”

Non-naturally Occurring Helical Molecules Can Interfere with p53–MDM2 and p53–MDMX Protein–Protein Interactions

“…Our further structural studies revealed that homooligomers of either cisor trans-amide can fold themselves into corresponding highly ordered helices. [4][5][6][7] Moreover, unlike α-amino acid peptides, which are significantly stabilized by intramolecular hydrogen bonding, these helical structures are self-organized and conformationally stable without the aid of hydrogen bonding and irrespective of solvent (protic/aprotic/halogenated) or temperature. Combination of these bicyclic β-proline analogues and α-amino acids, that is, heterooligomers are also synthetically accessible, and the N-amide bond of these bicyclic β-proline analogues are reluctant to alkaline hydrolysis, indicating some metabolic stability.…”