Sequence-specific protein–DNA interactions are crucial in processes such as DNA organization, gene regulation and DNA replication. Thor van Heesch, Peter Bolhuis and Jocelyne Vreede have developed a molecular simulation approach to quantify the sequence specificity of protein–DNA complexes, that yields results fast, and is generally applicable to any protein–DNA complex. The approach is based on molecular dynamics simulations in combination with a sophisticated steering potential and results in an estimate of the free energy difference of dissociation. Our protocol facilitates quantitative prediction of protein–DNA complex stability, while also providing high resolution insights into recognition mechanisms.