Helicity Synchronization-Induced Kinetic Stabilization against Helix Inversion in Stapled Peptides: Effects of 310/α Block Sequence and Double-Stapling Topology

Abstract Communication between neighboring helical domains is central to biological function, yet dynamic interactions between distinct peptide helices remain poorly understood. Herein, we report a series of nonoverlapping doubly stapled block-type peptides composed entirely of achiral components and containing α-α, 310-310, α-310, and 310-α helical architectures. Despite their distinct geometries and hydrogen-bonding patterns, neighboring helical segments were found to communicate efficiently, resulting in exclusive formation of homochiral (P,P)- and (M,M)-helices. Reversing the order of the α- and 310-helical blocks produced a 5.5-fold difference in helix inversion rate, demonstrating that block sequence controls P/M interconversion kinetics. The nonoverlapping α-α architecture underwent P/M interconversion approximately 1600 times faster than the previously reported overlapping doubly stapled analogue, in which the staples partially overlap within a single helical domain, underscoring the importance of double-stapling topology. Nevertheless, tandem linkage of two dynamic helical domains also markedly enhanced kinetic stability; notably, the half-life of the α-α architecture was approximately 800 times longer than that of the corresponding singly stapled analogue. In addition, selected doubly stapled architectures exhibited pronounced self-induced diastereomeric anisochronicity (SIDAC), enabling direct real-time monitoring of molecular helicity and helix inversion by 1H NMR spectroscopy without external additives. These results demonstrate how communication between distinct peptide helices gives rise to emergent dynamic behavior and provide a general strategy for programming helical dynamics in abiotic peptide systems.