Implications of fast-time scale dynamics of human DNA/RNA cytosine methyltransferases (DNMTs) for protein function

The role of protein dynamics in the control of substrate recognition, catalysis, and protein-protein interactions is often underestimated. Recently, a number of studies have examined the contribution of protein dynamics to the thermodynamics of ligand binding in detail, mostly using NMR relaxation measurements and molecular dynamics (MD) simulations. The results unequivocally demonstrate that conformational dynamics play a pivotal role in the properties and functions of proteins, and ignoring this contribution is likely to lead to substantial errors when explaining the biological function of proteins and in predictions of the binding affinities of their cognate ligands. However, the details of the interplay between structure and dynamics and the way it affects the biological function of the target protein remain poorly understood. In this study, the changes in fast (picosecond-to-nanosecond time scale) dynamics of catalytic domains of four human cytosine DNA methyltransferases (DNMTs) were studied using molecular dynamics (MD) simulations. The results provide insight into the protein dynamics changes that occur upon binding of the cofactor, S-adenosylmethionine (SAM). Contrary to expectations, increased amplitude of motions of backbone amide (N-H) and terminal heavy atom (C-C) bond vectors was observed in all studied DNMTs upon binding of SAM. These results imply that the cofactor binding causes a global increase in the extent of protein dynamics in the short time scale. This global dynamic change constitutes a favourable entropic contribution to the free energy of SAM binding. These results suggest that cytosine DNA methyltransferases may exploit changes in their fast scale dynamics to reduce the entropic cost of the substrate binding.