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The Entropic Cost of Protein-Protein Association: A Case Study on Acetylcholinesterase Binding to Fasciculin-2

David D. L. Minh ^*, Jennifer M. Bui ^*, Chia-en Chang ^*, Tushar Jain ^*, Jessica M. J. Swanson ^* and J. Andrew McCammon ^* 

^* Howard Hughes Medical Institute, Center for Theoretical Biological Physics, Department of Chemistry and Biochemistry and Department of Pharmacology, University of California at San Diego, La Jolla, California

Correspondence: Address reprint requests and inquiries to David Minh, E-mail: dminh{at}mccammon.ucsd.edu.

Protein-protein association is accompanied by a large reduction in translational and rotational (external) entropy. Based on a 15 ns molecular dynamics simulation of acetylcholinesterase (AChE) in complex with fasciculin 2 (Fas2), we estimate the loss in external entropy using quasiharmonic analysis and histogram-based approximations of the probability distribution function. The external entropy loss of AChE-Fas2 binding, 30 cal/mol K, is found to be significantly larger than most previously characterized protein-ligand systems. However, it is less than the entropy loss estimated in an earlier study by A. V. Finkelstein and J. Janin, which was based on atomic motions in crystals.