A trick of the tail: computing the entropic contribution to the energetics of quinone-protein unbindung

We estimate the entropic contributions to the free energy of quinone unbinding in bacterial and mitochondrial respiratory chains using molecular dynamics (MD) and Monte Carlo (MC) computer simulations. For a varying length of the isoprenoid side chain, MD simulations in lipid bilayers and in unpolar solvents are used to assess the dihedral angle distributions along the chain. These form the basis of a MC estimate of the number of molecular structures that do not exhibit steric self-overlap and that are confined to the bilayer. We obtain an entropy drive of TΔS = 1.4 kcal mol^-1 for each isoprene unit, which in sum is comparable to the redox potential differences involved in respiratory chain electron transfer. We postulate an entropy-driven zipper for quinone unbinding and discuss it in the context of the bioenergetics and the structure of complex I, and we indicate possible consequences of our findings for MD-based free energy computations.