Stability and fluctuations of the potato carboxypeptidase A protein inhibitor fold: a molecular dynamics study.

A 120ps non-inertial solvent (NIS) molecular dynamics (MD) trajectory of the potato carboxypeptidase A protein inhibitor (PCI) was calculated and analyzed. It is shown that, in spite of a very low content of regular secondary structure, the PCI fold has a large degree of stability, judged from the fairly good agreement between the average MD and X-ray structures. The N-terminal and C-terminal regions behave differently, both in their isoatomic positional shifts with respect to the X-ray structure, and in atomic fluctuation pattern. Positional shifts up to 9A are detected in the exposed N-terminal region as it folds back on the inhibitor's core. This large deviation is most likely caused by the absence of the receptor protein or by the lack of supporting solvent molecules. In contrast, the C-terminal region, which is the primary contact site with the enzyme, has an average structure similar to the X-ray conformation; this feature is probably due to a hydrogen bond network to the central core of PCI. The C-terminal tail shows larger fluctuations than the core. The secondary contact site retains its structure in this simulation. The results evidence an intrinsically stable PCI fold which favors a spatially well defined, fairly flexible, structuration of the primary and secondary contact sites that optimizes PCI's interaction with its target enzyme.