A simple model for evolution of proteins towards the global minimum of free energy

Background: Proteins seem to have their native structure in a global minimum of free energy. No mechanism is known, however, for ensuring this property. Furthermore, computational complexity studies suggest that such a mechanism is not feasible. These seemingly contradictory observations can be reconciled by the suggestion that evolutionary selection can yield proteins whose native conformation is in the global minimum of free energy. The aim of this study is to investigate such evolutionary processes in a simple model of protein folding. Results: Three possible evolutionary processes are explored. First, if the free energy of the chain is kept below a fixed threshold there is no improvement towards the global minimum. Second, if free energy is minimized directly, sequences emerge whose native conformation is in the global minimum of free energy. Third, when evolutionary pressure is applied within a small set of close homologs, sequences emerge whose functional conformation is in the global minimum of free energy. Conclusions: Although minimizing free energy does select for sequences whose functional conformation is in the global free energy minimum, we argue that for most proteins, which typically have free energy values of only 5-15 kcal/mol, such evolutionary pressure cannot be considered biologically plausible. In contrast, by repeatedly forcing sequences to avoid drifting towards competing 'non-native' conformations, sequences emerge whose native conformation becomes very close to the global minimum of free energy. We argue that such a mechanism is both efficient and biologically plausible.