Physica A 353 (2005) 353–364 Stochastic strategy to analyze protein folding M.A. Moret a,b,Ã , P.M. Bisch c , E. Nogueira Jr. d , P.G. Pascutti c a CEPPEV - Fundac - a˜o Visconde de Cairu, 40226-900, Salvador, Bahia, Brazil b Departamento de Fı´sica, Universidade Estadual de Feira de Santana, 44031-460 Feira de Santana, Bahia, Brazil c Instituto de Biofı´sica, Universidade Federal do Rio de Janeiro, 21949-900 Rio de Janeiro, RJ, Brazil d Instituto de de Fı´sica, Universidade Federal da Bahia, 40210-340 Salvador, Bahia, Brazil Received 10 September 2004; received in revised form 20 December 2004 Available online 13 March 2005 Abstract We propose a stochastic approach to combine methods from computational physics and Tsallis statistics in order to analyze the potential energy hypersurface of the proteins. This approach enables us to study protein folding by the topology of the energy hypersurface close to the native structures. As a bonus, this stochastic procedure allows us to obtain some of the possible intermediate states of protein folding. In particular, we describe results which suggest that the enthalpy drives the process of protein folding close to the native state. Finally, we propose an alternative view of the process of protein folding. r 2005 Elsevier B.V. All rights reserved. PACS: 87.14.Cc; 05.45.Df; 87.15.Aa; 05.10.Ln Keywords: Secondary structure folding; Tsallis statistics; Generalized Simulated Annealing 1. Introduction Several empirical rules of protein folding can be deduced from information obtained from studies of protein in vitro [1]. Folding of small proteins in vitro is often complete within a few minutes [2]. Spectroscopic methods allow one to detect ARTICLE IN PRESS www.elsevier.com/locate/physa 0378-4371/$ - see front matter r 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.physa.2005.01.048 Ã Corresponding author. E-mail address: moret@cairu.br (M.A. Moret).