Understanding protein folding with energy landscape theory Part I: Basic concepts

Abstract

1. Introduction 1112. Levinthal's paradox and energy landscapes 1152.1 Including randomness in the energy function 1212.2 Some effects of energetic correlations between structurally similar states 1263. Resolution of problems by funnel theory 1283.1 Physical origin of free-energy barriers 1334. Generic mechanisms in folding 1384.1 Collapse, generic and specific 1394.2 Helix formation 1394.3 Nematic ordering 1414.4 Microphase separation 1425. Signatures of a funneled energy landscape 1456. Statistical Hamiltonians and self-averaging 1527. Conclusions and future prospects 1568. Acknowledgments 1579. Appendix: Glossary of terms 15710. References 158The current explosion of research in molecular biology was made possible by the profound discovery that hereditary information is stored and passed on in the simple, one-dimensional (1D) sequence of DNA base pairs (Watson & Crick, 1953). The connection between heredity and biological function is made through the transmission of this 1D information, through RNA, to the protein sequence of amino acids. The information contained in this sequence is now known to be sufficient to completely determine a protein's geometrical 3D structure, at least for simpler proteins which are observed to reliably refold when denatured in vitro, i.e. without the aid of any cellular machinery such as chaperones or steric (geometrical) constraints due to the presence of a ribosomal surface (for example Anfinsen, 1973) (see Fig. 1). Folding to a specific structure is typically a prerequisite for a protein to function, and structural and functional probes are both often used in the laboratory to test for the in vitro yield of folded proteins in an experiment.