Differences in dissociation free-energy profiles between cognate andnon-cognate protein-DNA complexes

Yonetani, Yoshiteru; Kono, Hidetoshi

DNA-binding proteins recognize cognate and non-cognate DNA sequences with two different binding modes, in which proteins loosely bind to non-cognate DNA sequences, but to cognate sequences they tightly bind. Experimental structures of such complexes provides us an atomic view of the binding modes, however, it is not so simple to dissect which is cognate or non-cognate complexes by seeing the structures. In this study, free-energy profiles for dissociation of a cognate and a non-cognate Lac repressor-DNA complexes were calculated to obtainen ergetic views by performing atomic-level molecular dynamics simulations. The results showed that the free energy profiles were clearly distinct between the cognate and non-cognate complexes. We found that this difference can be interpreted in terms of changes in the protein-DNA contacts and the number of interfacial hydration water. The calculated dissociation process here agrees with that suggested from an H/D exchange experiment. In the talk, we will discuss how gene regulatory proteins find their target sites on the DNA and what are determinants for distinguishing cognate and non-cognate targets.