Molecular dynamics simulations of interaction between protein-tyrosine phosphatase 1B and a bidentate inhibitor
Abstract
Aim: To investigate the dynamic properties of protein-tyrosine phosphatase (PTP)
1B and reveal the structural factors responsible for the high inhibitory potency
and selectivity of the inhibitor SNA for PTP1B. 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 PTP1B molecule decreases. The most notable change is the
movement of the WPD-loop. Our simulation results also indicated that electrostatic
interactions contribute more to PTP1B-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 designed
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).
Keywords:
1B and reveal the structural factors responsible for the high inhibitory potency
and selectivity of the inhibitor SNA for PTP1B. 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 PTP1B molecule decreases. The most notable change is the
movement of the WPD-loop. Our simulation results also indicated that electrostatic
interactions contribute more to PTP1B-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 designed
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).