Extending the capabilities of targeted molecular dynamics: Simulation of alarge conformational transition in plasminogen activator inhibitor 1

Kruger, P Verheyden, S Declerck, PJ Engelborghs, Y

P. Kruger et al., Extending the capabilities of targeted molecular dynamics: Simulation of alarge conformational transition in plasminogen activator inhibitor 1, PROTEIN SCI, 10(4), 2001, pp. 798-808

41

INGLESE

Article

Biochemistry & Biophysics

PROTEIN SCIENCE

0961-8368 → ACNP

10

4

2001

798 - 808

ISI

0961-8368(200104)10:4<798:ETCOTM>2.0.ZU;2-0

Plasminogen activator inhibitor type 1 (PAI-1) is an inhibitor of plasminog en activators such as tissue-type plasminogen activator or urokinase-type p lasminogen activator. For this molecule, different conformations are known. The inhibiting form that interacts with the proteinases is called the acti ve form. The noninhibitory, noncleavable form is called the latent form. X- ray and modeling studies have revealed a large change in position of the re active center loop (RCL), responsible for the interaction with the proteina ses, that is inserted into a beta -sheet (s4A) in the latent form. The mech anism underlying this spontaneous conformational change (half-life = 2 h at 37 degreesC) is not known in detail. This investigation attempts to predic t a transition path from the active to the latent structure at the atomic l evel, by using simulation techniques. Together with targeted molecular dyna mics (TMD), a plausible assumption on a rigid body movement of the RCL was applied to define an initial guess for an intermediate. Different pathways were simulated, from the active to the intermediate, from the intermediate to the latent structure and vice versa under different conditions. Equilibr ium simulations at different steps of the path also were performed. The res ults show that a continuous pathway from the active to the latent structure can be modeled. This study also shows that this approach may be applied in general to model large conformational changes in any kind of protein for w hich the initial and final three-dimensional structure is known.