A Single Stereodynamic Center Modulates the Rate of Self‐Assembly in a Biomolecular System

Abstract

Chirality is a property of asymmetry important to both physical and abstract systems. Understanding how molecular systems respond to perturbations in their chiral building blocks can provide insight into diverse areas, such as biomolecular self-assembly, protein folding, drug design, materials, and catalysis. Despite the fundamental importance of stereochemical preorganization in nature and designed materials, the ramifications of replacing chiral centers with stereodynamic atomic mimics in the context of biomolecular systems is unknown. Herein, we demonstrate that replacement of a single amino acid stereocenter with a stereodynamic nitrogen atom has profound consequences on the self-assembly of a biomolecular system. Our results provide insight into how the fundamental biopolymers of life would behave if their chiral centers were not configurationally stable, highlighting the vital importance of stereochemistry as a pre-organizing element in biomolecular folding and assembly events.

δ-Azaproline and Its Oxidized Variants

“…A similar enhancement of cis rotamer population was recently observed for γ-azaproline, while the conformational characteristics of γ-(dimethylsila)­proline closely mimic those of Pro . α-Azaproline, which harbors a stereodynamic α center, was recently accommodated within a well-folded all- trans collagen model system without significant energetic penalty …”

Structural Basis for Aza-Glycine Stabilization of Collagen

“…17 We posit that the nitrogen atoms in azGly adopt a planar sp 2 -like geometry similar to that of N-amidourea small molecules (see Figures S4−S8), in contrast to the sp 3 -like pyramidal geometry adopted by the nitrogen atoms in some sterically crowded semicarbazides. 12 Out of 11 structures containing the same azGly substructure, average values for ϕ were −112 ± 41°, ranging from −67 to −172°. Average values of ψ were −175 ± 8 and 173 ± 5°, appearing to have amide-like character and an inherent preference for the values needed to mimic collagen Gly residues.…”

“…10,11 Previous studies in our laboratory have demonstrated several effective modifications to the collagen backbone. 1,2,12,13 Notably, the substitution of glycine with aza-glycine (azGly, azG) was shown to enhance the stability of the collagen triple helix. 1,2 We have since used azGly substitution to stabilize several collagen model peptides (CMPs) made up of POG triplet repeat sequences.…”

“…Conversely, glycine (Gly, G) is strictly conserved. Glycine mutations lead to structural instability in the collagen triple helix and serve as the molecular basis of several diseases such as osteogenesis imperfecta. , Previous studies in our laboratory have demonstrated several effective modifications to the collagen backbone. ,,, Notably, the substitution of glycine with aza-glycine (azGly, azG) was shown to enhance the stability of the collagen triple helix. , We have since used azGly substitution to stabilize several collagen model peptides (CMPs) made up of POG triplet repeat sequences. However, specificity within the collagen protein–protein interactome comes from unique amino acid recognition sequences that deviate from the POG motif .…”

Synthetic Marine Sponge Collagen by Late-Stage Dihydroxylation

“…Typical concentrations are 50–500 μM and temperature gradients of 4–12 °C/h. These variations of experimental conditions lead to deviations of up to several degrees centigrade for similar CMPs. ,, NMR spectroscopy exploits the known phenomenon of the high-field shift of Pro Hδ (Xaa position) in the folded triple-helical form (red in Figure ). , …”