Computational modeling highlights the role of the disordered Formin Homology 1 domain in profilin-actin transfer.

Formins accelerate actin polymerization, assumed to occur through flexible Formin Homology 1 (FH1) domain-mediated transfer of profilin-actin to the barbed end. To study FH1 properties and address sequence effects, including varying length/distribution of profilin-binding proline-rich motifs, we performed all-atom simulations of a set of representative FH1 domains of formins: mouse mDia1 and mDia2, budding yeast Bni1 and Bnr1, and fission yeast Cdc12, For3, and Fus1. We find FH1 has flexible regions between high-propensity polyproline helix regions. A coarse-grained model retaining sequence specificity, assuming rigid polyproline segments, describes their size. Multiple bound profilins or profilin-actin complexes expand mDia1-FH1, which may be important in cells. Simulations of the barbed end bound to Bni1-FH1-FH2 dimer show that the leading FH1 can better transfer profilin or profilin-actin, with decreasing probability as the distance from FH2 increases.