Chemical physics of protein folding

In 2008, to the consternation of some, one of the editors of this special issue on the “Chemical Physics of Protein Folding,” was quoted as saying, “What was called the protein folding problem 20 years ago is solved” (1). One purpose of this special issue is to drive home this point. The other, more important purpose is to illustrate how workers on the protein folding problem, by moving beyond their early obsession with seeming paradoxes (2), are developing a quantitative understanding of how the simpler biological structures assemble both in vitro and in vivo. The emerging quantitative understanding reveals simultaneously the richness of folding phenomena and the elegant simplicity of the underlying principles of spontaneous biomolecular assembly. The appreciation of these contrasting aspects of the folding problem has come about through the cooperation of theorists and experimentalists, a theme common to all the contributions to this special issue. Although the basic ideas about the folding energy landscape have turned out to be quite simple, entering even into some undergraduate textbooks (3), exploring their consequences in real systems has required painstaking intellectual analysis, as well as detailed computer simulations and experiments that still stretch the bounds of what is feasible. The backgrounds of the contributors to this issue reflect the breadth of the folding field and range from computer science and theoretical physics to molecular biology and organic chemistry. A great deal of the progress in the field can thus be traced to a fairly successful effort to develop a common language and conceptual framework for describing folding.