The Allosteric Mechanism of Yeast Chorismate Mutase: A Dynamic Analysis

The effector-​regulated allosteric mechanism of yeast chorismate mutase (YCM) was studied by normal mode anal. and targeted mol. dynamics. The normal mode anal. shows that the conformational change between YCM in the R state and in the T state can be represented by a relatively small no. of low-​frequency modes. This suggests that the transition is coded in the structure and is likely to have a low energetic barrier. Quant. comparisons (i.e. frequencies) between the low-​frequency modes of YCM with and without effectors (modeled structures) reveal that the binding of Trp increases the global flexibility, whereas Tyr decreases global flexibility. The targeted mol. dynamics simulation of substrate analog release from the YCM active site suggests that a series of residues are crit. for orienting and "recruiting" the substrate. The simulation led to the switching of a series of substrate-​release-​coupled salt-​bridge partners in the ligand-​binding domain; similar changes occur in the transition between YCM R-​state and T-​state crystal structures. Thus, the normal mode anal. and targeted mol. dynamics results provide evidence that the effectors regulate YCM activity by influencing the global flexibility. The change in flexibility is coupled to the binding of substrate to the T state and release of the product from the R state, resp.