A Free Energy Pathway for the Interaction of the SRY Protein with Its Binding Site on DNA from Atomistic Simulations

The SRY gene on the Y chromosome is a necessary and sufficient condition for the development of the mate phenotype and is involved in sex-reversal pathologies. The associated SRY protein also represents a convenient model system for the study of indirect protein-DNA recognition mechanisms, in which the local plasticity of DNA may play a more important role than direct interactions between the protein and the DNA bases. Using a novel, low-bias restraint methodology, we have performed molecular dynamics simulations of the controlled dissociation of SRY from its cognate DNA sequence. The resulting free energy profile provides a detailed view of protein-DNA binding and identifies a metastable intermediate state.