"Nucleotide and Polymerization Effects on the Structure and Dynamics of Actin"
Abstract
Actin is one of the most highly conserved and abundant proteins found in eukaryotic cells. It participates in a vast number of protein-protein interactions, many of which are involved in the strict regulation of the polymerization and disassembly of actin filaments. Actin's affinity for these interactions, as well as for polymerization, are strongly dependent upon actin’s nucleotide state. To examine the effects of both nucleotide and polymerization on actin structure and dynamics, we performed multi-microsecond molecular dynamic simulations on both ADP and ATP α-muscle G-actin, as well as two of the most recent F-actin models (2ZWH and 3MFP). We find that the ADP and ATP G-actin monomers show large deviations from their crystal structures and show a clear nucleotide state dependence. Nucleotide-dependent changes have been identified in several regions that have previously been implicated, but also in regions of the target-binding cleft, such as the c-terminal hinge (A331-Y337) and the FQQ-loop (S348-W356), where the majority of actin binding proteins interact. The F-actin models show a more modest shift from their starting points, and surprisingly the conformational spaces of all simulations have significant overlap, suggesting that the G- and F-actin structures are more similar than previously thought. The F-actin simulations also reveal both structural and dynamic differences between the barbed and pointed ends that provide insight into differences in phosphate release and polymerization rates at the two ends of the filament.
