HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Krüger, P. Articles by Engelborghs, Y. Search for Related Content PubMed PubMed Citation Articles by Krüger, P. Articles by Engelborghs, Y. Social Bookmarking                   What's this?

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

¹ Laboratory of Biomolecular Dynamics, Katholieke Universiteit Leuven, 3001 Leuven, Belgium
² Laboratory for Pharmaceutical Biology and Phytopharmacology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium

Reprint requests to: Prof. Dr. Yves Engelborghs, Katholieke Universiteit Leuven, Laboratory of Biomolecular Dynamics, Celestijnenlaan 200D, 3001 Leuven, Belgium; e-mail: Yves.Engelborghs{at}fys.kuleuven.ac.be; fax: 32-1632-7982.

Plasminogen activator inhibitor type 1 (PAI-1) is an inhibitor of plasminogen activators such as tissue-type plasminogen activator or urokinase-type plasminogen activator. For this molecule, different conformations are known. The inhibiting form that interacts with the proteinases is called the active form. The noninhibitory, noncleavable form is called the latent form. X-ray and modeling studies have revealed a large change in position of the reactive center loop (RCL), responsible for the interaction with the proteinases, that is inserted into a ß-sheet (s4A) in the latent form. The mechanism underlying this spontaneous conformational change (half-life = 2 h at 37°C) is not known in detail. This investigation attempts to predict a transition path from the active to the latent structure at the atomic level, by using simulation techniques. Together with targeted molecular dynamics (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. Equilibrium simulations at different steps of the path also were performed. The results 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 which the initial and final three-dimensional structure is known.

Keywords: Targeted molecular dynamics; molecular dynamics simulation; conformational change; plasminogen activator inhibitor 1; serpin; pathway calculation

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. Verheyden, A. Sillen, A. Gils, P. J. Declerck, and Y. Engelborghs Tryptophan Properties in Fluorescence and Functional Stability of Plasminogen Activator Inhibitor 1 Biophys. J., July 1, 2003; 85(1): 501 - 510. [Abstract] [Full Text] [PDF]

				B. De Taeye, G. Compernolle, M. Dewilde, W. Biesemans, and P. J. Declerck Immobilization of the Distal Hinge in the Labile Serpin Plasminogen Activator Inhibitor 1: IDENTIFICATION OF A TRANSITION STATE WITH DISTINCT CONFORMATIONAL AND FUNCTIONAL PROPERTIES J. Biol. Chem., June 20, 2003; 278(26): 23899 - 23905. [Abstract] [Full Text] [PDF]