Unraveling the Structure of Cofilin Oligomers: Insights into Actomyosin Network regulation through Coarse-Grained Molecular Dynamics

The actin-binding protein cofilin occupies a pivotal role in the modulation of the actomyosin network dynamics. Through the effective severing of actin filaments and facilitation of actin monomer recycling, cofilin significantly contributes to the structural rearrangement of the cellular cytoskeleton. While extensive research has been conducted on cofilin's monomeric actin-severing form, previous experimental findings have also revealed cofilin's capability to assemble functionally distinct oligomers that play a role in actin nucleation and assembly. However, despite experimental observations of these functions, the precise structural conformations of cofilin oligomers remain undetermined. In this study, we conducted an exploration of potential cofilin dimer structures using molecular dynamics simulations performed on human cofilin 1 (PDB ID: 4BEX). The candidate dimers were denoted by the cysteine residues presented at their interfaces and exhibited unique population distributions and relative free energies. Notably, our simulations revealed that the experimentally proposed dimer 39-147 exhibited relatively unstable configurations. Conversely, a remarkable dimer 139-147 displayed stable free energy profiles and intriguing structural symmetry. Moreover, dimer 39-39 emerged as a promising candidate for the formation of cofilin tetramers, substantiated by frustration analysis of protein interactions. Furthermore, our docking simulations with actin filaments confirmed the stability of these cofilin-actin complexes. In conclusion, our findings establish a solid theoretical foundation for comprehending cofilin oligomerization, thereby enhancing our understanding of how actin-binding proteins regulate the dynamics of the actomyosin network.