MM 2006 An international conference of the Asia / Pacific Chapter MGMS 19 – 22 April 2006

Signal protein NtrC possesses a pre-existing conformational equilibrium encompassing both inactive and active states. It shows a positive heterotropic allostery in the single switch domain for binding ligands and phosphorylation. Using a coarse-grained dynamics simulation, we computed the fluctuations and correlations of inter-domain motion in NtrC. The diagonalized correlation between the inactive and active state indicates that the most fluctuating motion in the switch domain, upon phosphorylation, occurs around Asp54 and Thr82-Tyr101 (the so-called ‘Y-T’ coupling, as in Fig. 1). Phosphorylation induces the flexibility changes in the active site with alpha-helices 3 and 4 being pushed away from the active site. The changes make helix 3&4 more stable, and introduce an axial rotation in helix 4. This leads the conformation of the switch domain to the entropic favoured active state and increase binding capability for target ligands to the allosteric site. These structural and dynamical analyses provide unique insights into allosteric cooperativity in proteins. Figure 1. Crossed correlation of the inter-domain motions before/after the phosphorylation at the active site D54 (Asp54): a correlated motion (red) of the alpha-3 region occurs along with an anti-correlated motion (blue) of the active site region. Molecular and Brownian dynamics simulation of acetylcholine receptor channel gating