Roles of physical interactions in determining protein-folding mechanisms: molecular simulation of protein G and alpha spectrin SH3.
Protein-folding mechanisms of two small globular proteins, IgG binding domain of protein G and alpha 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 alpha 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 beta hairpin is formed earlier and is rigid, once ordered, in the presence of an intact C terminal turn. The alpha helix is found to exhibit repeated partial formations/deformations during folding and to be stabilized via the tertiary contact with preformed beta sheets. This predicted scenario is fully consistent with experimental phi 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 alpha spectrin SH3, we found that the distal beta 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.
Department of Chemical and Biomolecular Engineering and Center for Ultramicrochemical Process Systems, Korea Advanced Institute of Science and Technology, Guseong-dong, Yuseong-gu, Daejeon, Korea.
Seung Yup
SY
Lee
Yoshimi
Y
Fujitsuka
Do Hyun
DH
Kim
Shoji
S
Takada
D001426:Bacterial Proteins / Q000737:chemistry; D003198:Computer Simulation; D007074:Immunoglobulin G / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013049:Spectrin / Q000737:chemistry; D018909:src Homology Domains
D001426:Bacterial Proteins; C034284:IgG Fc-binding protein, Streptococcus; D007074:Immunoglobulin G; D013049:Spectrin