THEORY OF PROTEIN FOLDING: The Energy Landscape Perspective

Abstract

The energy landscape theory of protein folding is a statistical description of a protein's potential surface. It assumes that folding occurs through organizing an ensemble of structures rather than through only a few uniquely defined structural intermediates. It suggests that the most realistic model of a protein is a minimally frustrated heteropolymer with a rugged funnel-like landscape biased toward the native structure. This statistical description has been developed using tools from the statistical mechanics of disordered systems, polymers, and phase transitions of finite systems. We review here its analytical background and contrast the phenomena in homopolymers, random heteropolymers, and protein-like heteropolymers that are kinetically and thermodynamically capable of folding. The connection between these statistical concepts and the results of minimalist models used in computer simulations is discussed. The review concludes with a brief discussion of how the theory helps in the interpretation of results from fast folding experiments and in the practical task of protein structure prediction.

Identification and characterization of protein folding intermediates

“…Lately, a new view of protein folding has emerged, namely that proteins fold via parallel routes, which may be depicted as a flux of molecules along different folding channels partitioned by the relative effect of denaturant on the relevant transition states [39]. According to this model, intermediates are not necessary steps during the folding but rather kinetic traps due to the ruggedness of the folding landscape.…”

Hamming distance geometry of a protein conformational space: Application to the clustering of a 4‐ns molecular dynamics trajectory of the HIV‐1 integrase catalytic core

“…There are other approaches to data clustering but we employ hierarchichal methods because the energy landscape of a protein is supposed to consist of an hierarchical embedding of potential wells [17][18][19][20] .…”

Protein folding: Then and now

“…The concepts of the nucleation and the free energy landscape have promoted much of the recent progress in understanding the process of protein folding. Proteins are generally thought to have evolved to exhibit globally funneled energy landscapes [23][24][25] which allow proteins to fold to their native states through a stochastic process in which the free energy decreases spontaneously. The unfolded state, transition state, native state and possible intermediates correspond to local minima or saddle points in the free-energy landscape.…”