Folding and binding cascades: Dynamic landscapes and population shifts

Whereas previously we have successfully utilized the folding funnels concep t to rationalize binding mechanisms (Ma B, Kumar S, Tsai CJ, Nussinov R, 19 99, Protein Eng 12:713-720) and to describe binding (Tsai CJ, Kumar S, Ma B , Nussinov R, 1999, Protein Sci 8:1181-1190), here we further extend the co ncept of folding funnels, illustrating its utility in explaining enzyme pat hways, multimolecular associations, and allostery. This extension is based on the recognition that funnels are not stationary; rather, they are dynami c, depending on thr physical or binding conditions (Tsai CJ, Ma B, Nussinov R, 1999, PI-oc Natl Acad Sci USA 96:9970-9972). Different binding states c hange the surrounding environment of proteins. The changed environment is i n turn expressed in shifted energy landscapes, with different shapes and di stributions of populations of conformers. Hence, the function of a protein and its properties are not only decided by the static folded three-dimensio nal structure; they are determined by the distribution of its conformationa l substates, and in particular, by the redistributions of the populations u nder different environments. That is, protein function derives from its dyn amic energy landscape, caused by changes in its surroundings.