Solving the protein folding problems

Abstract

The protein folding problem persists in being the major unsolved problem in biophysics and molecular biology. The most immediate obstacle to its solution is said to be the immense combinatorial difficulty of finding the global minimum energy structure, due to the galactic number of possible rotamer states for the polypeptide backbone and its sidechains, the so-called Levinthal paradox1. Much attention has been paid to the topography of the free energy surface that the folding polypeptide has to negotiate in order to find this minimum and the notion of a funnel-shaped topography has been proposed2. While this has achieved wide acceptance, providing insight into the possible shape of the free energy surface, it still does not solve the problem. In this work it is suggested that, in order to proceed further with this line of enquiry, it would be useful to focus on not one but, rather, two of the free energy minima accessible to the folding polypeptide. These two minima are considered to represent the active and inactive, or resting, states of the protein. There is experimental evidence for this model and a well populated database of structures that is analysed in detail in this work.