Allosteric Inhibition Modulates SHP2 Diffusion Behavior from Rotational to Translational via C-SH2 Domain Stabilization

The rotational and translational diffusion behaviors of proteins are closely related to the processes of contact and complex formation between proteins. Previous studies have indicated that allosteric inhibitors of SH2 domain-containing phosphatase 2 (SHP2) could suppress its activation induced by the PD-1 protein. Nevertheless, the underlying mechanism governing this allosteric regulation remained poorly understood. In this study, we utilized nonequilibrium molecular dynamics (NEMD) simulations to investigate the potential relationship between the diffusion behavior of SHP2 and its allosteric regulation. We found that conformational fluctuations in the C-SH2 domain prevented SHP2 from maintaining a compact hydration structure, which consequently led to its rotational diffusion under hydrodynamic forces. The inhibitor could restrict the fluctuations of the C-SH2 domain, causing SHP2 to switch to a translational diffusion mode in solution. Moreover, the inhibitor reduced the local water density near the binding pocket, which diminished the propensity for the exposure of the SHP2 active site. Furthermore, we discovered that the translational diffusion of SHP2 reduced the flexibility of the protein–protein interaction interface, thereby increasing the difficulty of protein complex formation. These findings highlighted the intrinsic link between the protein structure and diffusion behavior, providing crucial molecular-level insights for modulating protein–protein interactions.