Abstract
F(O)F(1) ATP synthase, a ubiquitous enzyme that synthesizes most ATP in living cells, is composed of two rotary motors: a membrane-embedded proton-driven F(O) motor and a catalytic F(1) motor. These motors share both central and peripheral stalks. Although both F(O) and F(1) have pseudo-symmetric structures, their symmetries do not match. How symmetry mismatch is solved remains elusive because of the missing intermediate structures of the rotational steps. Here, for the case of Bacillus PS3 ATP synthases with three- and 10-fold symmetries in F(1) and F(O), respectively, we uncovered the mechanical couplings between F(O) and F(1) at every 36° rotation step via molecular dynamics simulations and comparative studies of cryoelectron microscopy (cryo-EM) structures from three species. We found that the mismatch could be solved using several elements: 1) the F(1) head partially rotates relative to the F(O) a subunit via elastic distortion of the b subunits, 2) the rotor is twisted, and 3) comparisons of cryo-EM structures further suggest that the c ring rotary angles can deviate from the symmetric ones. In addition, the F(1) motor may have non-canonical structures, relieving stronger frustration. Thus, we provide new insights for solving the symmetry mismatch problem.