by B. Fain Y. Xia M. Levitt Determination of optimal Chebyshev- expanded hydrophobic discrimination function for globular proteins We describe the development of a scoring function designed to model the hydrophobic effect in protein folding. An optimization technique is used to determine the best functional form of the hydrophobic potential. The scoring function is expanded using the Chebyshev polynomials, for which the coefficients are determined by minimizing the Z-score of native structures in the ensembles of alternate conformations. (The Z-score is the score relative to the mean, measured in units of standard deviation.) The derived effective potential is tested on decoy sets conventionally used in such studies. The function is able to discriminate very well between correct and incorrect folds, despite the fact that it simply counts the number of neighbors of each amino acid. Our results show that the techniques of Z-score optimization and Chebyshev expansion work, and work well. Our results also confirm that hydrophobic effect is one of the principal driving forces in protein folding. Introduction A potential function which distinguishes native and native- like conformations from non-native structures is essential to protein structure prediction [1–10]. In this work we present three major ideas, each of which is used to design a potential function. First, we define a very simple effective potential for protein Copyright 2001 by International Business Machines Corporation. Copying in printed form for private use is permitted without payment of royalty provided that (1) each reproduction is done without alteration and (2) the Journal reference and IBM copyright notice are included on the first page. The title and abstract, but no other portions, of this paper may be copied or distributed royalty free without further permission by computer-based and other information-service systems. Permission to republish any other portion of this paper must be obtained from the Editor. 0018-8646/01/$5.00 © 2001 IBM IBM J. RES. & DEV. VOL. 45 NO. 3/4 MAY/JULY 2001 B. FAIN ET AL. 525