Surfing on protein folding energy landscapes.

Abstract

The so-called new view of protein folding describes the process in terms of funnel-shaped energy landscapes (1, 2). In this view, the drive for a protein to fold to its native state originates from a strong slope of the energy landscape toward native conformations. However, this can be counteracted by roughness of the energy landscape that could render the folding reaction less effective, a phenomenon called frustration . A major question occupying the protein folding community in recent years is the relative importance of protein topology and sequence in determining the folding mechanism of proteins. In this issue of PNAS (3), Shea et al. investigate the contribution of protein topology and protein sequence to the frustration of energy landscapes. Shea et al. investigate the contribution of protein topology and protein sequence to the frustration of energy landscapes. More than 30 years have passed since the “Levinthal Paradox” (4) was formulated. Levinthal calculated that it is impossible for a polypeptide chain to find its native state by exploring the entire conformational space. Therefore, some kind of search Algorithm has to exist which led to the proposal that proteins fold via specific pathways to the native configuration. Different mechanisms for folding were proposed to solve the paradox. Because a detailed description of all of the models is outside the scope of this commentary, the three main lines of thought are briefly explored. In the nucleation-growth model , (5) one or more critical kinetic nuclei are formed, around which the rest of the structure grows. Another family of models, such as the framework model , (6) envisages the formation of secondary structure elements followed by the docking of those elements to form tertiary interactions in the rate limiting step. Finally, in the hydrophobic collapse model , (7) the hydrophobic effect is considered …