Roles of physical interactions in determining protein‐folding mechanisms: Molecular simulation of protein G and α spectrin SH3

AbstractProtein‐folding mechanisms of two small globular proteins, IgG binding domain of protein G and α spectrin SH3 domain are investigated via Brownian dynamics simulations with a model made of coarse‐grained physical energy functions responsible for sequence‐specific interactions and weak Gō‐like energies. The folding pathways of α spectrin SH3 are known to be mainly controlled by the native topology, while protein G folding is anticipated to be more sensitive to the sequence‐specific effects than native topology. We found in the folding of protein G that the C terminal β hairpin is formed earlier and is rigid, once ordered, in the presence of an intact C terminal turn. The α helix is found to exhibit repeated partial formations/deformations during folding and to be stabilized via the tertiary contact with preformed β sheets. This predicted scenario is fully consistent with experimental ϕ value data. Moreover, we found that the folding route is critically affected when the hydrophobic interaction is excluded from physical energy terms, suggesting that the hydrophobicity critically contributes to the folding propensity of protein G. For the folding of α spectrin SH3, we found that the distal β hairpin and diverging turn are parts formed early, fully in harmony with previous results of simple Gō‐like and experimental analysis, supporting that the folding route of SH3 domain is robust and coded by the native topology. The hybrid method provides useful tools for analyzing roles of physical interactions in determining folding mechanisms. Proteins 2004. © 2004 Wiley‐Liss, Inc.