Non-native Interactions Explain the Folding Rate Differences in α-Spectrin Domains and the Origin of Internal Friction Effects

Abstract

AbstractRecent experimental and computational studies have shown the influence of internal friction in protein folding dynamics. However, uncertainty remains over its molecular origin. α-spectrin experimental results indicate that R15 domain folds three orders of magnitude faster than its homologous R16 and R17. Such anomalous observations are usually attributed to the influence of internal friction on protein folding rates. To study this phenomenon, we carried out molecular dynamics simulations with structure-based Cα models, in which the folding process of α-spectrin domains was investigated by adding non-native interactions. The simulations take into account the hydrophobic and the electrostatic contributions separately. The folding time results have shown a qualitative agreement with experimental data. We have also investigated mutations in R16 and R17, and the simulation folding time results correlate with the observed experimental ones. We suggest that the origin of the internal friction emerges from a cooperativity effect of these non-native interactions.