Exploring the effect of E76K mutation on SHP2 cause gain‐of‐function activity by a molecular dynamics study

Abstract

Juvenile myelomonocytic leukemia (JMML), an invasive myeloproliferative neoplasm, is a childhood disease with very high clinical lethality. Somatic mutation E76K in SHP2 is the most commonly identified mutation found in up to 35% of patients with JMML. To investigate the effect of gain-of-function mutation-E76K on SHP2 activity, molecular dynamic simulations on the wild-type SHP2 (SHP2-WT) system and the mutated E76K (SHP2-E76K) system were performed. The evaluation of stability of these two systems indicated that the simulated trajectories were stable after simulation for 3 nanoseconds. The root mean square fluctuation and the per-residue root mean square deviation illustrated that there were two regions (residues Tyr 81-Glu 83 and Glu 258-Leu 261) in the wild-type system and the mutated system, which had large differences. The principal component analysis, dynamic cross correlation maps analysis, as well as secondary structure analysis suggested that the mutated E76K impacted the movement of these two regions in SHP2 protein. Furthermore, residue interaction network analysis, hydrogen bond occupancy, and binding free energies analysis were used to explain how the two regions were specifically affected by the mutant. The results indicated that the primary variances between SHP2-WT and SHP2-E76K were the different interactions between Glu/Lys 76 and Arg 265, Tyr 80 and Leu 77, Leu 77 and Tyr 81, Thr 73 and Glu 258, Ala 75 and Cys 259, Phe 71 and Tyr 81, Ala 75 and Glu 258, and Tyr 73 and Glu/Lys 76. Consequently, these findings here might provide insights into the increased activity in SHP2-E76K.

Gain-of-Function SHP2 E76Q Mutant Rescuing Autoinhibition Mechanism Associated with Juvenile Myelomonocytic Leukemia

“…Thus, PTPN11 is recognized as the first proto-oncogene . However, the activation mechanism for the following mutations has been explored using MD simulation by Wang et al − In the present study, we have explored the activation mechanism for the first time, induced by GOF-mutation (E76Q) in SHP2 protein using essential dynamics simulation approaches. This mutation has been identified in exon 3 with some additional mutations that encrypt the N-SH2 regulatory domain.…”

Isoflavonoid and Furanochromone Natural Products as Potential DNA Gyrase Inhibitors: Computational, Spectral, and Antimycobacterial Studies

“…In order to learn more about the conformational states of daidzein-GyrB, PCA analysis was carried out utilizing the 100 ns MD simulation trajectory. This method assisted in determining the Cα atoms’ overall combined motion, which was shown by the “ eigenvectors of the covariance matrix ” and supported by its eigenvalues. , Typically, the frequency of the eigenvectors with high eigenvalues could be used to determine the protein’s overall coordinated motion. , As depicted in Figure , the first 20 PC values of the daidzein-GyrB system accounted for 25.045% of the total variation in the 100 ns trajectory. Most of the variance in the initial protein conformational space distribution was captured by the first two eigenvectors (PC1 and PC2).…”

An Insight of RuBisCO Evolution through a Multilevel Approach

“…To have a better understanding of the dynamics of the three RuBisCO isoforms, cross-correlation analysis (DCCM) was used to evaluate the motions (shifts) of alpha (Cα) carbon atoms in the MD simulations of all systems [ 56 ]. Additionally, it provides useful information regarding the mutation effect on protein dynamics by analyzing how atomic shifts were correlated [ 57 , 58 ], and it was constructed using the Bio3D package from R-Project [ 21 ].…”

“…In Figure 4, the eNMA shows the consensus fluctuations are highlighted and reveal a conserved pattern among species and RuBisCO forms (Figure 4a,b). The three isoforms show a greater fluctuation in the N-terminal domain spanning the amino acid residues (51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68) between the secondary elements αB and βC (Figure 4a), which are functionally relevant for RbcL. Likewise, RuBisCO form III presents greater fluctuation (≥3 Å) with respect to form I and II (Figure 4a,b).…”