A molecular dynamics study of WPD-loop flexibility in PTP1B

Protein tyrosine Phosphatase 1B (PTP1B) is an important drug target for the treatment of type II diabetes and obesity. There are strong indications that a novel class of allosteric inhibitors act by preventing the closure of the WPD-loop [C. Wiesmann, K.J. Barr, J. Kung, J. Zhu, D.A. Erlanson, W. Shen, B.J. Fahr, M. Zhong, L. Taylor, M. Randall, R.S. McDowell, S.K. Hansen, Allosteric inhibition of protein tyrosine Phosphatase 1B, Nat. Struc. Mol. Biol. 11 (2004) 730-737.], which is absolutely essential for the catalytic activity of PTP1B. In this work, we develop force field parameters for one of these inhibitors (BB3), and subsequently utilise standard and targeted molecular dynamics simulations to perform a study of WPD-loop mobility in the presence of this inhibitor. We demonstrate that BB3 not only significantly reduces the flexibility of the WPD-loop compared to both the apo-enzyme or the closed conformation complexed with phosphotyrosine, but that this is accompanied by reduced flexibility in a related region, the S-loop, further emphasising the possibility of manipulating this region when designing novel inhibitors for PTP1B.