Structure‐based thermodynamic analysis of the dissociation of protein phosphatase‐1 catalytic subunit and microcystin‐LR docked complexes

Open Access
Publisher Website
Google Scholar
Abstract
The relationship between the structure of a free ligand in solution and the structure of its bound form in a complex is of great importance to the understanding of the energetics and mechanism of molecular recognition and complex formation. In this study, we use a structure‐based thermodynamic approach to study the dissociation of the complex between the toxin microcystin‐LR (MLR) and the catalytic domain of protein phosphatase‐1 (PP‐lc) for which the crystal structure of the complex is known. We have calculated the thermodynamic parameters (enthalpy, entropy, heat capacity, and free energy) for the dissociation of the complex from its X‐ray structure and found the calculated dissociation constant (4.0 × 10−11) to be in excellent agreement with the reported inhibitory constant (3.9 × 10−11). We have also calculated the thermodynamic parameters for the dissociation of 47 PP‐1c:MLR complexes generated by docking an ensemble of NMR solution structures of MLR onto the crystal structure of PP‐1c. In general, we observe that the lower the root‐mean‐square deviation (RMSD) of the docked complex (compared to the X‐ray complex) the closer its free energy of dissociation (δG°d) is to that calculated from the X‐ray complex. On the other hand, we note a significant scatter between the δG°d and the RMSD of the docked complexes. We have identified a group of seven docked complexes with δG°d values very close to the one calculated from the X‐ray complex but with significantly dissimilar structures. The analysis of the corresponding enthalpy and entropy of dissociation shows a compensation effect suggesting that MLR molecules with significant structural variability can bind PP‐1c and that substantial conformational flexibility in the PP‐1c:MLR complex may exist in solution.