Preferred drifting along the DNA major groove and cooperative anchoring of the p53 core domain: mechanisms and scenarios.

While the importance of specific p53-DNA binding is broadly accepted, the recognition process is still not fully understood. Figuring out the initial tetrameric p53-DNA association and the swift and cooperative search for specific binding sites is crucial for understanding the transactivation mechanism and selectivity. To gain insight into the p53-DNA binding process, here we have carried out explicit solvent molecular dynamic (MD) simulations of several p53 core domain-DNA conformations with the p53 and the DNA separated by varying distances. p53 approached the DNA, bound non-specifically, and quickly drifted along the DNA surface to find the major groove, cooperatively anchoring in a way similar to the specific binding observed in the crystal structure. Electrostatics was the major driving force behind the p53 movement. Mechanistically, this is a cooperative process: key residues, particularly Lys120 and Arg280 acted as sensors; upon finding their hydrogen-bonding partners, they lock in, anchoring p53 into the major groove. Concomitantly, the DNA adopted a conformation that facilitated p53 easy access. The initial non-specific core domain-DNA contacts assist in shifting the DNA and the p53 substrates toward conformations "ready" for specific major groove binding, with subsequent optimization of the interactions. This work is an invited contribution for the special issue of the Journal of Molecular Recognition dedicated to Professor Martin Karplus.