PDZ Binding to the BAR Domain of PICK1 is Elucidated by Coarse-grained Molecular Dynamics

JOURNAL OF MOLECULAR BIOLOGY

卷:405

Article

He, Yi¹  Liwo, Adam^1,2  Weinstein, Harel³  Scheraga, Harold A.¹ 

[1] Cornell Univ, Baker Lab Chem & Chem Biol, Ithaca, NY 14853 USA

[2] Univ Gdansk, Fac Chem, PL-80952 Gdansk, Poland

[3] Cornell Univ, Dept Physiol & Biophys, Weill Cornell Med Coll, New York, NY 10065 USA

关键词: PICK1;    binding;    hydrophobic interactions;    UNRES force field;    molecular dynamics;   

DOI  :  10.1016/j.jmb.2010.10.051

来源: Elsevier

【 摘 要 】

A key regulator of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor traffic, PICK1 is known to interact with over 40 other proteins, including receptors, transporters and ionic channels, and to be active mostly as a homodimer. The current lack of a complete PICK1 structure determined at atomic resolution hinders the elucidation of its functional mechanisms. Here, we identify interactions between the component PDZ and BAR domains of PICK1 by calculating possible binding sites for the PDZ domain of PICK1 (PICK1-PDZ) to the homology-modeled, crescent-shaped dimer of the PICK1-BAR domain using multiplexed replica-exchange molecular dynamics (MREMD) and canonical molecular dynamics simulations with the coarse-grained UNRES force field. The MREMD results show that the preferred binding site for the single PDZ domain is the concave cavity of the BAR dimer. A second possible binding site is near the N-terminus of the BAR domain that is linked directly to the PDZ domain. Subsequent short canonical molecular dynamics simulations used to determine how the PICK1-PDZ domain moves to the preferred binding site on the BAR domain of PICK1 revealed that initial hydrophobic interactions drive the progress of the simulated binding. Thus, the concave face of the BAR dimer accommodates the PDZ domain first by weak hydrophobic interactions and then the PDZ domain slides to the center of the concave face, where more favorable hydrophobic interactions take over. (c) 2010 Elsevier Ltd. All rights reserved.

【 授权许可】

Free