A new approach for investigating protein flexibility based on Constraint Logic Programming. The first application in the case of the estrogen receptor.

摘要

We describe the potential of a novel method, based on Constraint Logic Programming (CLP), developed for an exhaustive sampling of protein conformational space. The CLP framework proposed here has been tested and applied to the estrogen receptor, whose activity and function is strictly related to its intrinsic, and well known, dynamics. We have investigated in particular the flexibility of H12, focusing on the pathways followed by the helix when moving from one stable crystallographic conformation to the others. Millions of geometrically feasible conformations were generated, selected and the traces connecting the different forms were determined by using a shortest path algorithm. The preliminary analyses showed a marked agreement between the crystallographic agonist-like, antagonist-like and hypothetical apo forms, and the corresponding conformations identified by the CLP framework. These promising results, together with the short computational time required to perform the analyses, make this constraint-based approach a valuable tool for the study of protein folding prediction. The CLP framework enables one to consider various structural and energetic scenarious, without changing the core algorithm. To show the feasibility of the method, we intentionally choose a pure geometric setting, neglecting the energetic evaluation of the poses, in order to be independent from a specific force field and to provide the possibility of comparing different behaviours associated with various energy models.