Intrinsically disordered proteins (IDP) are a broad class of proteins with relatively flat energylandscapes showing a high level of functional promiscuity, which are frequently regulatedthrough post-translational covalent modifications. Histone tails, which are the terminalsegments of the histone proteins, are prominent IDPs that are implicated in a variety ofsignaling processes, which control chromatin organization and dynamics. Although a largebody of work has been done on elucidating the roles of post-translational modifications infunctional regulation of IDPs, molecular mechanisms behind the observed behaviors arenot fully understood. Using extensive atomistic molecular dynamics simulations, we foundin this work that H4 tail mono-acetylation at LYS-16, which is a key covalent modification,induces a significant reorganization of the tail’s conformational landscape, inducing partialordering and enhancing the propensity for alpha-helical segments. Furthermore, our calculationsof the potentials of mean force between the H4 tail and a DNA fragment indicatethat contrary to the expectations based on simple electrostatic reasoning, the Lys-16mono-acetylated H4 tail binds to DNA stronger than the unacetylated protein. Based onthese results, we propose a molecular mechanism for the way Lys-16 acetylation mightlead to experimentally observed disruption of compact chromatin fibers.