Topological Frustration and the Folding of Interleukin-1b

0022-2836/$ see front matter q 2005 E Abbreviations used: IL-1b, interle molecular dynamics; MC, multicano relative contact order; lrc, long rang E-mail address of the correspond [email protected] The cytokine, interleukin-1b (IL-1b), adopts a b-trefoil fold. It is known to be much slower folding than similarly sized proteins, despite having a low contact order. Proteins are sufficiently well designed that their folding is not dominated by local energetic traps. Therefore, protein models that encode only the folded structure and are energetically unfrustrated (Gō-type), can capture the essentials of the folding routes. We investigate the folding thermodynamics of IL-1b using such a model and molecular dynamics (MD) simulations. We develop an enhanced sampling technique (a modified multicanonical method) to overcome the sampling problem caused by the slow folding. We find that IL-1b has a broad and high free energy barrier. In addition, the protein fold causes intermediate unfolding and refolding of some native contacts within the protein along the folding trajectory. This “backtracking” occurs around the barrier region. Complex folds like the b-trefoil fold and functional loops like the b-bulge of IL-1b can make some of the configuration space unavailable to the protein and cause topological frustration. q 2005 Elsevier Ltd. All rights reserved.