2026-10-12T22:59:59Z https://api.figshare.com/v2/oai

oai:figshare.com:article/33950761 2026-09-21T07:14:36Z category_1 category_4 category_915 category_12 category_21 category_24 category_734 category_135 portal_63 item_type_3 month_year_09_2026

Helicity Synchronization-Induced Kinetic Stabilization against Helix Inversion in Stapled Peptides: Effects of 3₁₀/α Block Sequence and Double-Stapling Topology Naoki Ousaka (1878280) Biophysics Biochemistry Physical Sciences not elsewhere classified Cell Biology Biotechnology Evolutionary Biology Biological Sciences not elsewhere classified Computational Biology yet dynamic interactions single helical domain programming helical dynamics neighboring helical segments neighboring helical domains induced kinetic stabilization induced diastereomeric anisochronicity emergent dynamic behavior block sequence controls abiotic peptide systems helix inversion rate α architecture underwent stapling topology communication 1 </ sup stapling topology helix inversion α architecture time monitoring tandem linkage stapled peptides results demonstrate molecular helicity interconversion kinetics helicity synchronization general strategy fold difference exclusive formation distinct geometries communicate efficiently bonding patterns biological function achiral components 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 (<i>P</i>,<i>P</i>)- and (<i>M</i>,<i>M</i>)-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 <i>P</i>/<i>M</i> interconversion kinetics. The nonoverlapping α-α architecture underwent <i>P</i>/<i>M</i> 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. 2026-09-21T00:00:00Z Dataset Dataset 10.1021/jacs.6c14108.s002 https://figshare.com/articles/dataset/Helicity_Synchronization-Induced_Kinetic_Stabilization_against_Helix_Inversion_in_Stapled_Peptides_Effects_of_3_sub_10_sub_Block_Sequence_and_Double-Stapling_Topology/33950761 CC BY-NC 4.0