S. Rennebaum; A. Caflisch

Journal: Proteins
Year: 2012
Volume: 80
Issue: 8
Pages: 1998-2008
DOI: 10.1002/prot.24088
Type of Publication: Journal Article

Actins; Adenosine Triphosphate; Animals; Bicyclo Compounds, Heterocyclic; Binding Sites; Humans; Molecular Dynamics Simulation; Protein Conformation; Protein Multimerization; Protein Structure, Tertiary; Rabbits; Thiazolidines; Water


As part of the cytoskeleton, actin is essential for the morphology, motility, and division of eukaryotic cells. Recent X-ray fiber diffraction studies have shown that the conformation of monomeric actin is flattened upon incorporation into the filament by a relative rotation of its two major domains. The antiproliferative activity of latrunculin, a macrolide toxin produced by sponges, seems to be related to its binding to monomeric actin and inhibition of polymerization. Yet, the mechanism of inhibition is not known in detail. Here, multiple explicit water molecular dynamics simulations show that latrunculin binding hinders the conformational transition related to actin polymerization. In particular, the presence of latrunculin at the interface of the two major domains of monomeric actin reduces the correlated displacement of Domain 2 with respect to Domain 1. Moreover, higher rotational flexibility between the two major domains is observed in the absence of ATP as compared to ATP-bound actin, offering a possible explanation as to why actin polymerizes more favorably in the absence of nucleotides.