A Molecular Simulation Study to Investigate Actin Filament Elongation Mechanism

Abstract

Actin is a protein responsible for numerous cellular functions, for example, it is associated with the muscle contraction. Globular actin (G-actin) polymerizes into filamentous actin (F-actin). In the elongation process of the filament, actin hydrolyzes ATP into ADP. The rates of elongation at the pointed and barbed ends are different, and the latter end is the main elongation direction. The two planes defined by two near-axial pairs of domains are known to be relatively twisted (propeller angle ∼20°) in G-actin whereas those in F-actin are flat (∼5°). The atomic structure of F-actin has recently been determined by electron cryomicroscopy; however, the filament elongation mechanism is not fully understood yet at molecular level. In this work, we performed molecular dynamics simulations of G- and F-actins to investigate the elongation mechanism. As models for the terminal regions of F-actin, pentamer, hexamer, and heptamer of actin protomers were adopted. We examined the conformational changes of G-actin at the terminal of F-actin. The analysis of the propeller angle showed that G-actin bound to ATP tended to take the twisted form whereas ADP-bound G-actin was relatively flat. In addition, the salt bridge patterns near the hinge regions were significantly different between the ATP and ADP bound forms. Therefore, the propeller angle rotation is correlated with these salt bridges. The pentamer consisting of ADP-bound protomers was found to maintain the flat form. No notable change was observed in the propeller angles of the oligomer when one actin bound ATP was attached to the barbed end but significant change was induced for actin at the end when two ATP-bound actin molecules were attached to the pentamer at the barbed end, suggesting that protomer-protomer interaction between ATP-bound actin might be key for the elongation.