The nucleation mechanism of protein folding: a survey of computer simulation studies

The nucleation mechanism of protein folding, originally proposed by Baldwin in the early 1970s, was firstly observed by Shakhnovich and co-workers two decades later in the context of Monte Carlo simulations of a simple lattice model. At about the same time the extensive use of φ-value analysis provided the first experimental evidence that the folding of Chymotrypsin-inhibitor 2, a small single-domain protein, which folds with two-state kinetics, is also driven by a nucleation mechanism. Since then, the nucleation mechanism is generally considered the most common form of folding mechanism amongst two-state proteins. However, recent experimental data has put forward the idea that this may not necessarily be so, since the accuracy of the experimentally determined φ values, which are used to identify the critical (i.e. nucleating) residues, is typically poor. Here, we provide a survey of in silico results on the nucleation mechanism, ranging from simple lattice Monte Carlo to more sophisticated off-lattice molecular dynamics simulations, and discuss them in light of experimental data.