Under physiological conditions, many polypeptide chains spontaneously fold into discrete and tightly packed three‐dimensional structures. The folded polypeptide chain conformation is believed to represent a minimum Gibbs energy of the system, governed by the weak interactions that operate between the amino acid residues and between the residues and the solvent. A semiempirical molecular thermodynamic model is proposed to represent the Gibbs energy of folding of aqueous homopolypeptide systems. The model takes into consideration both the entropy contribution and the enthalpy contribution of folding homopolypeptide chains in aqueous solutions. The entropy contribution is derived from the Flory‐Huggins expression for the entropy of mixing. It accounts for the entropy loss in folding a random‐coiled polypeptide chain into a specific polypeptide conformation. The enthalpy contribution is derived from a molecular segment‐based Non‐Random Two Liquid (NRTL) local composition model [H. Renon and J. M. Prausnitz (1968) AIChE J., Vol. 14, pp. 135–142; C.‐C. Chen and L. B. Evans (1986) AIChE J., Vol. 32, pp. 444–454], which takes into consideration of the residue‐residue, residue‐solvent, and solvent‐solvent binary physical interactions along with the local compositions of amino acid residues in aqueous homo‐polypeptides. The UNIFAC group contribution method [A. Fredenslund, R. L. Jones, and J. M. Prausnitz (1975) AIChE J., 21, 1086–1099; A. Fredenslund, J. Gmehling, and P. Rasmussen (1977) Vapor‐Liquid Equilibrium Using UNIFAC, Elsevier Scientific Publishing Company, Amsterdam], developed originally to estimate the excess Gibbs energy of solutions of small molecules, was used to estimate the NRTL binary interaction parameters. The model yields a hydrophobicity scale for the 20 amino acid side chains, which compares favorably with established scales [Y. Nozaki and C. Tanford (1971) Journal of Biological Chemistry, Vol. 46, pp. 2211–2217; E. B. Leodidis and T. A. Hatton (1990) Journal of Physical Chemistry, Vol. 94, pp. 6411–6420]. In addition, the model generates qualitatively correct thermodynamic constants and it accurately predicts thermodynamically favorable folding of a number of aqueous homopolypeptides from random‐coiled states into α‐helices. The model further facilitates estimation of the Zimm‐Bragg helix growth parameter s and the nucleation parameter s for amino acid residues [B. H. Zimm and J. K. Bragg (1959) Journal of Chemical Physics, Vol. 31, pp. 526–535]. The calculated values of the two parameters fall into the ranges suggested by Zimm and Bragg. © 1992 John Wiley & Sons, Inc.