Decoding the selective mechanism behind a monobody inhibitor to the phosphatase domain of SHP2: insights from molecular dynamics simulations

The Src-homology 2 (SH2) domain-containing phosphatase 2 (SHP2), encoded by PTPN11, is a critical tyrosine phosphatase that regulates key cellular processes, including cell proliferation, survival, and migration. The catalytic activity of its protein tyrosine phosphatase (PTP) domain plays a pivotal role in cancer progression by activating oncogenic signaling pathways. In contrast, SHP1, another SH2 phosphatase encoded by PTPN6, generally functions as a tumor suppressor. Given their structural similarity yet distinct biological functions, developing selective SHP2-PTP inhibitors is crucial for targeted cancer therapy. Recently, a monobody, Mb (SHP2PTP_13) (Mb13), has been designed to bind to the SHP2-PTP structure specifically. However, the detailed mechanism involved in selective inhibition remains to be clarified. To achieve this objective, we conducted extensive molecular dynamics simulations of the Mb13-SHP2-PTP and Mb13-SHP1-PTP systems, together with multiple analyses, including cluster analysis, principal component analysis, free energy landscape evaluation, a cross-correlation matrix and binding free energy calculation. Our results demonstrated that Mb13 bound more stably to SHP2-PTP compared to SHP1-PTP. The SHP2 complex exhibited conformational stability and reduced flexibility, indicating a more substantial interaction. Detailed analysis revealed that key residues within SHP2-PTP formed more robust interactions with Mb13, enhancing the complex's overall stability. These findings suggested that the selective binding mechanism was primarily driven by specific stabilizing interactions at the molecular level. Overall, the enhanced understanding of SHP2-PTP's binding dynamics and stability offers valuable guidance for advancing drug design strategies targeting SHP2-mediated pathways.