Relationships Between Unfolded Configurations of Proteins and Dynamics of Folding to the Native State ATTILA GURSOY, OZLEM KESKIN, METIN TURKAY, BURAK ERMAN College of Engineering and Center for Computational Biology and Bioinformatics, Koc ¸ University, . Istanbul 34450, Turkey Received 26 April 2006; revised 18 July 2006; accepted 4 August 2006 DOI: 10.1002/polb.21018 Published online in Wiley InterScience (www.interscience.wiley.com). ABSTRACT: We compare folding trajectories of chymotrypsin inhibitor (CI2) using a dynamic Monte Carlo scheme with Go-type potentials. The model considers the four back- bone atoms of each residue and a sphere centered around C b the diameter of which is cho- sen according to the type of the side group. Bond lengths and bond angles are kept fixed. Folding trajectories are obtained by giving random increments to the u and w torsion angles with some bias toward the native state. Excluded volume effects are considered. Two sets of 20 trajectories are obtained, with different initial configurations. The first set is generated from random initial configurations. The initial configurations of the second set are generated according to knowledge-based neighbor dependent torsion probabilities derived from triplets in the Protein Data Bank. Compared to chains with randomly gen- erated initial configurations, those generated with neighbor-dependent probabilities (i) fold faster, (ii) have better defined secondary structure elements, and (iii) have less num- ber of non-native contacts during folding. V V C 2006 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 44: 3667–3678, 2006 Keywords: chymotrypsin inhibitor; folding trajectories; go-type model; Monte-Carlo simulation; protein folding dynamics INTRODUCTION The unfolded state of proteins has important role on the folding process and on the stability of the folded state. 1 The unfolded state is now being rec- ognized as the ‘other half’ of the protein folding equation. 2 In this paper, we show, by a dynamic Monte Carlo and statistical mechanical analysis and by using knowledge-based torsion potentials, that the unfolded state is not random. Important correlations exist between the torsion angles in the unfolded state. These correlations are impor- tant because they stabilize fragments of secondary structure and reduce the number of initial confor- mations available to the protein chain. We show that the conformations that survive in the unfolded state have significantly larger number of native-like contacts compared to those in chains subject to random potentials and this affects the folding rate significantly. There is growing evidence, both theoretical and experimental, that the unfolded configurations of proteins are not random, and that a significant amount of structure is present that resembles the structure of the folded native state. 2–4 Recent fluo- rescence resonance energy transfer experiments on nascent proteins point out to the fact that proteins have native-like conformations even in the ribo- some. 5 The fact that the unfolded state is not as het- erogeneous as it was thought to be has been pointed out in several earlier studies. 6–8 The presence of native-like features in the unfolded protein has im- portant consequences concerning its folding into its native state. As pointed out by several authors, 2,3,6 Correspondence to: B. Erman (E-mail: berman@ku.edu.tr) Journal of Polymer Science: Part B: Polymer Physics, Vol. 44, 3667–3678 (2006) V V C 2006 Wiley Periodicals, Inc. 3667