Estimates protein–DNA binding energies from in vivo binding profiles. TherMos is a position specific energy matrix (PSEM) estimation method. The software infers an additive binding energy model using least-squares fitting to the ChIP-seq tag profile. TherMos fits to the peak shape in binding regions, rather than to absolute peak height. It can also be used on ChIP-exo data, which provides even higher spatial resolution than ChIP-seq.