Branching Suppresses Self-Aggregation while Preserving Membrane Association in SET-M33: An Atomistic Molecular Dynamics Study
- 1Istituto Italiano di Tecnologia
Abstract
Branched antimicrobial peptides offer a promising strategy for improving the stability and activity of membrane-active peptides, but how branching alters self-association and membrane binding remains unclear. We used all-atom molecular dynamics simulations to compare tetra-branched SET-M33 with its linear branch sequence Q33 (KKIRVRLSA) in water and at an anionic bacterial-membrane model, to do this, systems containing equivalent numbers of Q33 sequence units were simulated. Q33 formed dimers and higher-order oligomers, particularly at the membrane interface and under hydration-tuned enhanced sampling. In contrast, SET-M33 remained more dispersed, as the branched scaffold and its high cationic charge limited peptide-peptide association while allowing multivalent membrane binding. Both architectures associated rapidly with the bilayer but remained predominantly surface-bound, without persistent pore formation or complete insertion. Q33 showed stronger membrane-induced helical stabilization, whereas SET-M33 retained a more heterogeneous conformational ensemble. Overall, branching primarily altered lateral peptide organization while preserving close membrane association, suppressing uncontrolled self-aggregation and providing an atomistic rationale for the distinct behavior of SET-M33 relative to Q33.
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BibTeX
@misc{satvati2026branching,
title = {{Branching Suppresses Self-Aggregation while Preserving Membrane Association in SET-M33: An Atomistic Molecular Dynamics Study}},
author = {S. Satvati and M. Rigoli and S. Fortuna and C. Falciani and A. Pini and W. Rocchia},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.12.757849},
url = {https://www.biorxiv.org/content/10.64898/2026.10.12.757849v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Branching Suppresses Self-Aggregation while Preserving Membrane Association in SET-M33: An Atomistic Molecular Dynamics Study
AU - S. Satvati
AU - M. Rigoli
AU - S. Fortuna
AU - C. Falciani
AU - A. Pini
AU - W. Rocchia
PY - 2026
DA - 2026/10/12
PB - bioRxiv
DO - 10.64898/2026.10.12.757849
UR - https://www.biorxiv.org/content/10.64898/2026.10.12.757849v1
AB - Branched antimicrobial peptides offer a promising strategy for improving the stability and activity of membrane-active peptides, but how branching alters self-association and membrane binding remains unclear. We used all-atom molecular dynamics simulations to compare tetra-branched SET-M33 with its linear branch sequence Q33 (KKIRVRLSA) in water and at an anionic bacterial-membrane model, to do this, systems containing equivalent numbers of Q33 sequence units were simulated. Q33 formed dimers and higher-order oligomers, particularly at the membrane interface and under hydration-tuned enhanced sampling. In contrast, SET-M33 remained more dispersed, as the branched scaffold and its high cationic charge limited peptide-peptide association while allowing multivalent membrane binding. Both architectures associated rapidly with the bilayer but remained predominantly surface-bound, without persistent pore formation or complete insertion. Q33 showed stronger membrane-induced helical stabilization, whereas SET-M33 retained a more heterogeneous conformational ensemble. Overall, branching primarily altered lateral peptide organization while preserving close membrane association, suppressing uncontrolled self-aggregation and providing an atomistic rationale for the distinct behavior of SET-M33 relative to Q33.
ER -