The Interplay between Structural Stability and Plasticity Determines Mutation Profiles and Chaperone Dependence in Protein Kinases

• DOI: 10.1021/acs.jctc.7b00997
• Publication Date: 2017-12-21T01:08:58Z
• Authors: Antonella Paladino; Filippo Marchetti; Luca Ponzoni; Giorgio Colombo
• Keywords: 0301 basic medicine; Protein Conformation; Protein Stability; 610; proteine kinase; stability; Molecular Dynamics Simulation; 03 medical and health sciences; Mutation; Humans; HSP90 Heat-Shock Proteins; chaperone hsp 90; Protein Kinases; Molecular Chaperones

We present a novel comparative analysis of representative protein kinases to characterize the main dynamic and energetic determinants of functional regulation shared among different families. The relationships between stability and plasticity are also used to rationalize kinase tendencies to interact with the molecular chaperone Hsp90. These questions are tackled through newly developed molecular-dynamics-based methods of analysis of internal energy and dynamics applied to a total of 37 different systems, which represent wild-type and mutated proteins, including active and inactive states. Energetic decomposition analysis is coupled to multiple structural alignments and dynamic decomposition methods and identifies, across different families, common elements that underlie fold stabilization and conformational regulation. This analysis also exposes which substructures play a key role in determining chaperone dependence. Overall, the results highlight common interaction networks that underpin kinase stabilization, are modulated by mutations (even if located at a distance), and underlie their tendencies to act as clients or nonclients of Hsp90.