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Cancer-Associated Actin Mutations Enhance Cofilin Binding Affinity: Insights from Steered Molecular Dynamics Simulations

Authors :

Danial Sedighpour¹ Farzan Ghalichi² Iman Zoljanahi Oskui³

1- دانشگاه صنعتی سهند 2- دانشگاه صنعتی سهند 3- دانشگاه صنعتی سهند

Keywords :

Actin Mutations،Cofilin،Steered Molecular Dynamics (SMD)،Interaction Energy،Binding Affinity

Abstract :

Cofilin plays a pivotal role in remodeling of the actin cytoskeleton by binding to actin filaments and facilitating their severing and depolymerization. Alterations in cofilin-actin interactions due to actin mutations have been implicated in various cancers, including skin cancer. This study investigates the binding affinity of cofilin to both wild-type (WT) and mutant actin (D288N, G168N, R63Q) using steered molecular dynamics (SMD) simulations. Structural models were constructed and subjected to constant velocity pulling to measure maximum rupture forces and interaction energies. Results demonstrate that all three cancer-associated mutations exhibit increased rupture forces and more negative total energy compared to WT, indicating stronger binding affinities. Notably, the R63Q mutation produced the highest rupture force and most favorable interaction energies, suggesting a significant stabilizing effect on the actin-cofilin complex. These findings provide critical insight into the molecular effects of oncogenic actin mutations and their potential role in cytoskeletal dysregulation during cancer progression.