A Physics-Based Approach for Understanding Foldability

Abstract

Statistical coupling analysis (SCA) indicates that in addition to the conservation of amino acid composition at individual site, the coupling information between sites is necessary and sufficient to specify a protein fold.[1] To investigate the significance of coupling information, we simulate a repertoire of artificial WW domain sequences using a physics-based search method called ZAM (Zipping and Assembly method).[2] Our result shows that coupling information has a remarkable influence on the local contacts of N-terminal β-turn of WW domains. This turn would not form correctly if lack of such information. Interestingly, the formation of N-terminal β-turn has been determined as the nucleator and rate-limiting step experimentally.[3] We also identify specific crucial contacts at the beginning of folding process, and accomplish to predict the foldability of a WW sequence, based on its favor of these crucial contacts.1. Socolich M, Lockless SW, Russ WP, Lee H, Gardner KH, Ranganathan R. 2005. Evolutionary information for specifying a protein fold. Nature 437: 5122. Ozkan SB, Wu GA, Chodera JD, Dill KA. 2007. Protein folding by zipping and assembly. Proceedings of the National Academy of Sciences of the United States of America 104: 119873. Jager M, Nguyen H, Crane JC, Kelly JW, Gruebele M. 2001. The folding mechanism of a beta-sheet: The WW domain. Journal of Molecular Biology 311: 373