# Agent-based modelling of the early stages of actin polymerisation required to drive endocytosis in Saccharomyces cerevisiae

## TL;DR

This paper uses a computational model to study how actin polymerization drives endocytosis in yeast, revealing new insights into the process.

## Contribution

The study introduces an agent-based model that simulates actin filament generation during endocytosis in yeast, revealing novel mechanistic insights.

## Key findings

- Las17 must form multimeric complexes for effective actin polymerization.
- De novo F-actin nucleation occurs in two stages involving linear trimer formation followed by rapid polymerization.
- Competition between SH3 domains and other factors is critical for on/off switching during actin polymerization.

## Abstract

Endocytosis is critical. Its complexity means that many aspects remain poorly understood. We have developed an agent-based model covering key components of actin filament generation in endocytosis in Saccharomyces cerevisiae. The model incorporates realistic values for rates, affinities, concentrations, and mobilities, and reproduces essential features of endocytosis, from the arrival of WASp/Las17 and its inhibitor Sla1 at the membrane up to the burst of actin polymerisation. The model yields relative rates and affinities for interactions that cannot be measured experimentally, and places limitations on plausible scenarios. Specifically, it reveals three novel findings. First, Las17 must form multimeric complexes. Second, de novo F-actin nucleation occurs in two stages, involving the slow formation of linear trimers, followed by rapid polymerisation once an additional actin monomer is positioned at the side of the aligned monomers. Third, competition between SH3 domains and other factors, including actin, is critical to ensure on/off switching. This requires: (1) tandem domains binding to adjacent polyproline sites outcompeting single domains; (2) these tandem domains being weakened in overall affinity through a reduction in avidity by competition with single SH3 domains. We conclude with a pathway that proposes how controlled actin polymerisation occurs, and raises implications for further testing.

The online version contains supplementary material available at 10.1038/s41598-025-14248-w.