The Effects of Inhibitor Chivosazole A on Actin Interacting with Profilin: A Theoretical Study

Actin is highly conserved and contributes to numerous cellular activities. Profilin, one of actin binding proteins, promotes the exchange rate of nucleotide of actin, which leads to a fast elongation of actin filament. To slow down the elongation of filament, chivosazole A (ChivoA) is developed as an inhibitor of blocking actin‐profilin interaction. Intriguingly, known from the solved crystal structure, ChivoA does not bind on the interface between actin and profilin. Here, molecular dynamics (MD) simulation is used to study the possible mechanism how ChivoA inhibits actin‐profilin interaction. First, principal component analysis and representative structures comparisons reveal that the conformation of ChivoA‐bound actin is restrained at a closed state, whereas a trend toward an open state is found in profilin‐bound actin. Then, Peptide Gaussian accelerated MD shows that ChivoA limits the ability of the DNase I binding loop (D‐loop) swings and enlarges a distance between two major profilin binding regions. On the contrary, the distance between these two regions of profilin‐bound actin decreases in a clamp‐like motion mode. Finally, binding energies are calculated by molecular mechanics/poisson‐boltzmann surface area method and display that the ChivoA‐bound actin is less favorable for profilin binding.