Molecular dynamics simulations of interaction between protein-tyrosine phosphatase 1B and a bidentate inhibitor

Aim： To investigate the dynamic properties of protein-tyrosine phosphatase （PTP） IB and reveal the structural factors responsible for the high inhibitory potency and selectivity of the inhibitor SNA for PTPIB. Methods： We performed molecular dynamics （MD） simulations using a long time-scale for both PTP1B and PTP1B complexed with the inhibitor SNA, the most potent and selective PTP1B inhibitor reported to date. The trajectories were analyzed by using principal component analysis. Results： Trajectory analyses showed that upon binding the ligand, the flexibility of the entire PTPIB molecule decreases. The most notable change is the movement of the WPD-loop. Our simulation results also indicated that electrostatic interactions contribute more to PTP 1B-SNA complex conformation than the van der Waals interactions, and that Lys41, Arg47, and Asp48 play important roles in determining the conformation of the inhibitor SNA and in the potency and selectivity of the inhibitor. Of these, Arg47 contributed most. These results were in agreement with previous experimental results. Conclusion： The information presented here suggests that potent and selective PTP1B inhibitors can be de- signed by targeting the surface residues, for example the region containing Lys41, Arg47, and Asp48, instead of the second phosphate binding site （besides the active phosphate binding site）.