Transfer of Noncovalent Chiral Information along an Optically Inactive Helical Peptide Chain: Allosteric Control of Asymmetry of the C-Terminal Site by External Molecule that Binds to the N-Terminal Site

Abstract

This study aims at demonstrating end-to-end transfer of noncovalent chiral information along a peptide chain. The domino-type induction of helical sense is proven by using achiral peptides 1-m of bis-chromophoric sequence with different chain lengths: H-(Aib-Delta(Z)Phe)(m)-(Aib-Delta(Z)Bip)(2)-Aib-OCH(3) [m = 2, 4, and 6; Aib = alpha-aminoisobutyric acid; Delta(Z)Phe = (Z)-alpha,beta-didehydrophenylalanine; Delta(Z)Bip = (Z)-beta-(4,4'-biphenyl)-alpha,beta-didehydroalanine]. They all showed the tendency to adopt a 3(10)-helix. Whereas peptide 1-m originally shows no circular dichroism (CD) signals, marked CD signals were induced at around 270-320 nm based on both the beta-aryl didehydroresidues by chiral Boc-proline (Boc = tert-butoxycarbonyl). The observed CD spectra were interpreted on the basis of the exciton chirality method and theoretical CD simulation of several helical conformations that were energy-minimized. The experimental and theoretical CD analysis reveals that Boc-l-proline induces the preference for a right-handed helicity in the whole chain of 1-m. Such noncovalent chiral induction was not observed in the corresponding N-terminally protected 1-m. Obviously, helicity induction in 1-m originates from the binding of Boc-proline to the N-terminal site. In the 17-mer (1-6), the information of helix sense reaches the 16th residue from the N-terminus. We have monitored precise transfer of noncovalent chiral stimulus along a helical peptide chain. The present study also proposes a primitive allosteric model of a single protein-mimicking backbone. Here chiral molecule binding the N-terminal site of 1-6 controls the chiroptical signals and helical sense of the C-terminal site about 30 A away.

Ligand-modulated conformational switching in a fully synthetic membrane-bound receptor

“…Synthetic molecules have been designed that have functional analogy with ligand-activated GPCRs like the β2 adrenoreceptor, 1 but they work only in organic solvents. [13][14][15][16] Results and Discussion Design of the receptor mimic. We set out to design and construct a synthetic molecular structure exhibiting the 'minimal' essential design features required for a functional mimic of a ligand-activated GPCR.…”

“…Other analytical techniques typically used for conformational analysis of foldamers in solution [14][15][16] were found to be ill-suited to the membrane phase and/or Cu(II) ions. Pyrene has a monomer fluorescence emission at 378 nm, and depending on their proximity and relative orientation, a pair of pyrene fluorophores may form an excimer that emits at 450 nm.…”

End-to-end conformational communication through a synthetic purinergic receptor by ligand-induced helicity switching

“…Synthetic molecules designed to mimic the architecture and binding properties of biopolymers are now commonplace, with examples including peptoids 3 , peptide-nucleic acids 4 , amide foldamers 5 and anti-sense nucleotides 6 . However, synthetic mimics of dynamic, switchable structures, capable of translating information about ligand binding into remote conformational consequences, are much rarer [7][8][9] .…”

“…Configurationally achiral helical foldamers necessarily populate equally left-handed (M) and right-handed (P) screw-sense conformers, but the equilibrium between these conformers is sensitive to subtle chiral influences. The screwsense of helical polymers 12,13 can be controlled by relatively few chiral monomers among many achiral ones (the 'sergeants and soldiers' principle) 14,15 or by coordination to chiral counterions 9,16,17 .…”

“…It is well established that a single chiral residue sited at the terminus of an otherwise achiral helical oligomer is sufficient to bias the screw-sense of the oligomer [18][19][20][21][22] , and remote spectroscopic reporters have been used to detect the resulting conformational preference 9,[21][22][23][24][25][26][27] . Helical oligomers may consequently behave as communication devices, because the relayed conformational change allows stereochemistry at one end of the oligomer to influence a reporter several nanometres away 28 .…”