How a single mutation alters the protein structure: a simulation investigation on protein tyrosine phosphatase SHP2

Area of Science:

• Biochemistry and Molecular Biology
• Structural Biology
• Computational Biology

Background:

• Protein tyrosine phosphatase SHP2 (SHP2) is crucial for numerous signaling pathways.
• An oncogenic mutation, E76K, alters SHP2's conformation from closed to open, activating the enzyme.

Purpose of the Study:

• To investigate the conformational dynamics of SHP2.
• To understand the impact of the E76K mutation on SHP2's conformational ensemble.

Main Methods:

• Extensive molecular dynamics (MD) simulations.
• Metadynamics (MetaD) simulations were employed to explore conformational landscapes.

Main Results:

• The E76K mutation promotes a preference for the open, active conformation of SHP2.
• Conformational transitions between closed and open states are collective processes.
• Intermediate metastable states during these transitions were identified.

Conclusions:

• The E76K mutation stabilizes the active conformation of SHP2.
• Understanding these conformational dynamics aids in designing targeted SHP2 inhibitors.