Exploring the effects of hydrogen bonding and hydrophobic interactions on the foldability and cooperativity of helical proteins using a simplified atomic model

Using a simplified atomic model, we perform Langevin dynamics simulations of polypeptide chains designed to fold to one-, two- and three-helix native conformations. The impact of the relative strengths of the hydrophobic and hydrogen bonding interactions on folding is investigated. Provided that the two interactions are appropriately balanced, a simple potential function allows the chains to fold to their respective target native structures, which are essentially lowest-energy conformations. However, if the hydrophobic interaction is too strong, helix formation is preempted by hydrophobic collapse into compact conformations with little helical content. While the transition from denatured to compact non-native conformations is not cooperative, the transition between native (helical) and denatured states exhibits certain cooperative features. The degree of apparent cooperativity increases with the length of the polypeptide; but it falls far short of that observed experimentally for small, single-domain 'two-state' proteins. Even for the three-helix bundle, the present model interaction scheme leads to a distribution of energy which is not bimodal, although a heat capacity peak associated with thermal unfolding is observed. This finding suggests that models with simple pairwise additive interaction schemes, involving hydrophobic interactions and hydrogen bonding, can mimic the folding of small helical proteins, but that such models are insufficient to produce high degrees of folding cooperativity. Certain features of our model are reminiscent of a recent scenario proposed for downhill folding. Their ramifications are discussed