Computational insights into the effect of mutation on actin-actin dimer and actin-related binding protein...

Actin, a key cytoskeletal protein, is essential for cellular processes including division, migration, and morphological regulation. Mutations in actin are linked to structural and functional defects associated with diseases such as skin cancer. However, the molecular mechanisms by which these mutations disrupt actin-actin interactions and binding with actin-regulatory proteins remain poorly understood. The current study employed steered molecular dynamics (SMD) simulations to investigate how skin cancer-associated actin mutations (D288N, G44R, G168N, R41Q, and R63Q) alter the mechanical stability of the actin-actin dimers and actin-binding proteins profilin and cofilin. Results revealed that all mutations except R63Q in lateral dimers significantly decreased the maximum unbinding force and stiffness of actin-actin dimers compared to wild-type (WT). Electrostatic interactions contributed dominantly (>85%) to dimer interaction energy. The G168N mutant exhibited the most severe reduction in dimer interaction energy (-456 kJ mol^-1 longitudinally; -376 kJ mol^-1 laterally), indicating structural destabilization. Furthermore, D288N and G168N mutants showed stronger interaction with cofilin (interaction energy -1591 kJ mol^-1 and -1771 kJ mol^-1, respectively), potentially promoting aberrant actin depolymerization during cancer progression. Interaction with profilin was enhanced in the D288N mutant but weakened in G168N, reflecting mutation-specific modulation of actin dynamics. These findings provide molecular-level insights into how actin mutations compromise filament mechanics and regulatory interactions, elucidating cytoskeletal alterations underlying cancer invasiveness and establishing a foundation for therapeutic exploration.