Cation-Induced Molecular Switching Based on Reversible Modulation of Peptoid Conformational States

Abstract

Peptoids are oligomers of N-substituted glycines with predictable folding and strong potentials as guest-binding receptor molecules. In this contribution, we investigate the structural features of a series of designed symmetric cyclic octamer peptoids (with methoxyethyl/propargyl side chains) as free hosts and reveal their morphologic changes in the presence of sodium and alkylammonium guests as tetrakis[3,5-bis(trifluoromethyl)phenyl]borate salts, reporting the first case of reversible adaptive switching between defined conformational states induced by cationic guests (Na and benzylammonium ion) in the peptoid field. The reported results are based on H NMR data, theoretical models, and single-crystal X-ray diffraction analysis. They represent initial steps toward deciphering the unique conformational states of cyclic octamer peptoids as supramolecular hosts with the aim to fully disclose their functional and dynamic properties.

The Challenge of Conformational Isomerism in Cyclic Peptoids

“…15/16 kcal mol –1 ), , with ϕ and ψ torsion angles within the expected energetic minima (ϕ ≈ ±70°, ψ ≈ ±175°), as in cyclo‐( N ph‐ N ph‐ N pa‐ N me) 2 , cyclo‐( N pa 8 ), cyclo‐( N spe 8 ), a propylazido derivative, congeners of cyclodepsipeptides, cyclo‐( N me 8 ), 6a / 6b , and cyclo‐(Sar 8 ), ( 8a / 8b , Figure A). It is interesting to note that the two trans ‐amide and the two cis ‐amide bonds of the octameric backbone form independent consecutive PPII and PPI helices, justifying the surprising conformational stability of these large cyclooligomers. The two C 2 ‐symmetric enantiomorphic conformational isomers of cyclo‐(Sar 8 ) ( 8a / 8b ) reported in Figure A, display opposite planar chirality configurations ( 8a : cyclo‐[( cis , p S )Sar 1 ‐( cis , p R )Sar 2 ‐( trans , p S )Sar 3 ‐( trans , p S )Sar 4 ] 2 , 8b : cyclo‐[( cis , p R )Sar 1 ‐( cis , p S )Sar 2 ‐( trans , p R )Sar 3 ‐( trans , p R )Sar 4 ] 2 ).…”

“…A further proof of the existence of conformational enantiomers 5a / 5b , and 6a / 6b came from single‐crystal X‐ray diffraction data where both mirror‐images were evident in the crystal packing (Figure ).…”

“…This is the case of asymmetric cyclohexamers 5a / 5b (i.e. : cyclo‐[( cis , p S ) N Phe 1 ‐( cis , p R ) N Val 1 ‐( trans , p R ) N Phe 2 ‐( cis , p R ) N Val 2 ‐( cis , p S ) N Phe 3 ‐( trans , p S ) N Val 3 ], cyclo‐[( cis , p R ) N Phe 1 ‐( cis , p S ) N Val 1 ‐( trans , p S ) N Phe 2 ‐( cis , p S ) N Val 2 ‐( cis , p R ) N Phe 3 ‐( trans , p R ) N Val 3 ], respectively) and of C 2 ‐symmetric octamers 6a / 6b (Figure ).…”

“…In more than ten years from the brilliant work by Kent Kirshenbaum and co‐workers, cyclic peptoids gained the status of key bioactive/biomimetic agents, efficient catalysts, promising supramolecular building‐blocks, and rigid scaffold/topological templates …”

Peptoids as tools and sensors

“…Schettini et al . used the same peptoid side‐chains (Nme, Npa) in cyclo‐octamer assemblies to explore the cation‐enabled reversible switching between two defined conformational states—a change from C 2 to C 8 symmetry upon sodium or benzylammonium cation complexation.…”