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Flexibility of Aromatic Residues in the Active-Site Gorge of Acetylcholinesterase: X-ray versus Molecular Dynamics

Yechun Xu ^* , Jacques-Philippe Colletier  , Martin Weik , Hualiang Jiang ^¶ ||, John Moult ^**, Israel Silman  and Joel L. Sussman ^*

^* Department of Structural Biology and Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel; University of California, Los Angeles-Department of Energy Institute of Genomics and Proteomics, University of California, Los Angeles, California 90095; Laboratoire de Biophysique Moléculaire, Institute de Biologie Structurale, 38027 Grenoble, France; ^¶ Center for Drug Discovery and Design, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; ^|| School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; and ^** Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, Rockville, Maryland 20850

Correspondence: Address reprint requests to Joel L. Sussman, Dept. of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel. Tel.: 972-8-934-4531; Fax: 972-8-934-4159; E-mail: Joel.Sussman{at}weizmann.ac.il.

The high aromatic content of the deep and narrow active-site gorge of acetylcholinesterase (AChE) is a remarkable feature of this enzyme. Here, we analyze conformational flexibility of the side chains of the 14 conserved aromatic residues in the active-site gorge of Torpedo californica AChE based on the 47 three-dimensional crystal structures available for the native enzyme, and for its complexes and conjugates, and on a 20-ns molecular dynamics (MD) trajectory of the native enzyme. The degree of flexibility of these 14 aromatic side chains is diverse. Although the side-chain conformations of F330 and W279 are both very flexible, the side-chain conformations of F120, W233, W432, Y70, Y121, F288, F290 and F331 appear to be fixed. Residues located on, or adjacent to, the -loop (C67–C94), namely W84, Y130, Y442, and Y334, display different flexibilities in the MD simulations and in the crystal structures. An important outcome of our study is that the majority of the side-chain conformations observed in the 47 Torpedo californica AChE crystal structures are faithfully reproduced by the MD simulation on the native enzyme. Thus, the protein can assume these conformations even in the absence of the ligand that permitted their experimental detection. These observations are pertinent to structure-based drug design.