Deciphering the Cofilin Oligomers via Intermolecular Disulfide Bond Formation: A Coarse-Grained Molecular Dynamics Approach to Understanding Cofilin’s Regulation on Actin Filaments

Cofilin, a key actin-binding protein, orchestrates the
dynamics
of the actomyosin network through its actin-severing activity and
by promoting the recycling of actin monomers. Recent experiments suggest
that cofilin forms functionally distinct oligomers via thiol post-translational
modifications (PTMs) that promote actin nucleation and assembly. Despite
these advances, the structural conformations of cofilin oligomers
that modulate actin activity remain elusive because there are combinatorial
ways to oxidize thiols in cysteines to form disulfide bonds rapidly.
This study employs molecular dynamics simulations to investigate human
cofilin 1 as a case study for exploring cofilin dimers via disulfide
bond formation. Utilizing a biasing scheme in simulations, we focus
on analyzing dimer conformations conducive to disulfide bond formation.
Additionally, we explore potential PTMs arising from the examined
conformational ensemble. Using the free energy profiling, our simulations
unveil a range of probable cofilin dimer structures not represented
in current Protein Data Bank entries. These candidate dimers are characterized
by their distinct population distributions and relative free energies.
Of particular note is a dimer featuring an interface between cysteines
139 and 147 residues, which demonstrates stable free energy characteristics
and intriguingly symmetrical geometry. In contrast, the experimentally
proposed dimer structure exhibits a less stable free energy profile.
We also evaluate frustration quantification based on the energy landscape
theory in the protein–protein interactions at the dimer interfaces.
Notably, the 39–39 dimer configuration emerges as a promising
candidate for forming cofilin tetramers, as substantiated by frustration
analysis. Additionally, docking simulations with actin filaments further
evaluate the stability of these cofilin dimer-actin complexes. Our
findings thus offer a computational framework for understanding the
role of thiol PTM of cofilin proteins in regulating oligomerization,
and the subsequent cofilin-mediated actin dynamics in the actomyosin
network.