(189aq) Gating Mechanisms during Actin Filament Elongation By Formins

Formins are large multidomain proteins that play important role in the polymerization of actin filaments and can slow down polymerization by 5 to 95% depending on the particular type of formin. Our aim in this work is to identify factors that influence polymerization of actin by examining three types of formins with different actin polymerization rates, namely mDia1, Bni1 and Cdc12. We use multiscale computational modeling approach and enhanced free energy sampling simulation techniques to examine the interactions between each of these formins and an actin filament. The simulations reveal key dissimilarities in the structures and intermolecular interactions of the three formin-actin complexes. We identify two factors that influence the rate of formin mediated actin polymerization. Firstly, steric clashes at the barbed end of the actin filament block the addition of new actin subunits. Secondly, interactions between formins and actin filament affect the configuration of the barbed end by flattening the helical twist of the terminal actin subunits. Larger distortion in the terminal actin subunits makes the barbed end less favorable for subunit addition. We discover that the ability of each type of formin to slow down actin filament elongation correlates with both its degree of flattening of the barbed end and steric blocking.