Computational exploration of the self-aggregation mechanisms of phenol-soluble modulins β1 and β2 in Staphylococcus aureus biofilms

Huan Xu; Xiaohan Zhang; Zhongyue Lv; Fengjuan Huang; Yu Zou; Chuang Wang; Feng Ding; Yunxiang Sun

doi:10.1016/j.colsurfb.2025.114498

Computational exploration of the self-aggregation mechanisms of phenol-soluble modulins β1 and β2 in Staphylococcus aureus biofilms

Colloids Surf B Biointerfaces. 2025 Jan 5:248:114498. doi: 10.1016/j.colsurfb.2025.114498. Online ahead of print.

Authors

Huan Xu¹, Xiaohan Zhang¹, Zhongyue Lv², Fengjuan Huang³, Yu Zou⁴, Chuang Wang⁵, Feng Ding⁶, Yunxiang Sun⁷

Affiliations

¹ School of Physical Science and Technology, Ningbo University, Ningbo 315211, China.
² Department of Neurology, the Affiliated LiHuiLi Hospital of Ningbo University, Ningbo 315211, China.
³ Ningbo Institute of Innovation for Combined Medicine and Engineering (NIIME), the Affiliated LiHuiLi Hospital of Ningbo University, Ningbo 315211, China.
⁴ Department of Sport and Exercise Science, Zhejiang University, Hangzhou 310058, China.
⁵ School of Basic Medical Science, Health Center, Ningbo University, Ningbo, Zhejiang 315211, China. Electronic address: wangchuang@nbu.edu.cn.
⁶ Department of Physics and Astronomy, Clemson University, Clemson, SC 29634, United States. Electronic address: fding@clemson.edu.
⁷ School of Physical Science and Technology, Ningbo University, Ningbo 315211, China; Department of Physics and Astronomy, Clemson University, Clemson, SC 29634, United States. Electronic address: sunyunxiang@nbu.edu.cn.

PMID: 39778221
DOI: 10.1016/j.colsurfb.2025.114498

Abstract

The formation of functional bacterial amyloids by phenol-soluble modulins (PSMs) in Staphylococcus aureus is a critical component of biofilm-associated infections, providing robust protective barriers against antimicrobial agents and immune defenses. Clarifying the molecular mechanisms of PSM self-assembly within the biofilm matrix is essential for developing strategies to disrupt biofilm integrity and combat biofilm-related infections. In this study, we analyzed the self-assembly dynamics of PSM-β1 and PSM-β2 by examining their folding and dimerization through long-timescale atomistic discrete molecular dynamics simulations. Our findings revealed that both peptides primarily adopt helical structures as monomers but shift to β-sheets upon dimerization. Monomeric state, PSM-β1 exhibited frequent transitions between helical and β-sheet forms, while PSM-β2 largely retained a helical structure. Upon dimerization, both peptides showed pronounced β-sheet formation around conserved C-terminal residues 21-44. Residues 21-33, largely unstructured as monomers, demonstrated strong tendencies for β-sheet formation and intermolecular interactions, underscoring their central role in the self-assembly of both peptides. Additionally, the PSM-β1 N-terminus formed β-sheets only when interacting with the C-terminus, whereas the PSM-β2 N-terminus remained helical and uninvolved in β-sheet formation. These distinct aggregation behaviors likely contribute to biofilm dynamics, with C-terminal regions facilitating biofilm formation and N-terminal regions influencing stability. Targeting residues 21-33 in PSM-β1 and PSM-β2 offers a promising therapeutic approach for disrupting biofilm integrity. This study advances our understanding of PSM-β1 and PSM-β2 self-assembly and presents new targets for drug design against biofilm-associated diseases.

Keywords: Aggregation; Conformational dynamics; Discrete molecular dynamics simulations; Phenol-soluble modulins; Self-assembly.