Protein dynamics and structural waters in bromodomains

Bromodomains are epigenetic readers of acetylated lysines that are integral parts of histone tails. The 61 bromodomains in humans are structurally highly conserved but specifically bind to widely varying recognition motifs, suggesting that dynamic rather than static factors are responsible for recognition selectivity. To test this hypothesis, the dynamics of the binding sites and structural water molecules of four bromodomains (ATAD2, BAZ2B, BRD2(1) and CREBBP) representing four different subtypes is studied with 1 μs MD simulations using the RSFF2 force field. The different dynamics of the ZA-loops and BC-loops between the four bromodomains leads to distinct patterns for the opening and closing of the binding pocket. This in turn determines the structural and energetic properties of the structural waters in the binding pocket, suggesting that these waters are not only important for the recognition itself, as has been proposed previously, but also contribute to the selectivity of different bromodomains.