Ser133 phosphate-KIX interactions in the CREB-CBP complex: an ab initio molecular dynamics study.

Cyclic AMP response element binding protein (CREB) is involved in activation of transcriptional DNA machinery by binding to the coactivator CREB-binding protein (CBP). The interactions between CREB serine phosphate (pSer133) and specific CBP residues (Tyr658 and Lys662) play a crucial role for the thermodynamic stability of the CREB-CBP complex. Here we use ab initio methods to investigate the dynamics and energetics of a relatively large, fully hydrated model complex representing pSer133 and its counterparts of the CBP domain. The calculations suggest that: (1) key contributions to the stabilization of the complex arise not only from electrostatics (as previously proposed) but also from a previously unrecognized "low-barrier hydrogen bond" between pSer133 and Lys662; (2) hydration plays a crucial role for the stabilization of the phosphate charge; (3) formation of the complex involves a significant degree of reorganization of the electronic charge density.