Many proteins contain cofactors, such as heme, ATP and metal ions. Binding of cofactors is not only essential for their biological functions, but also can reshape the intrinsic energy landscape of protein molecules and modulate the folding and stability. However, the molecular mechanism of cofactor coupled protein folding is not well understood. In this work, we study the cofactor coupled folding of myoglobin, which is a typical cofactor (heme) containing protein, by performing molecular dynamics simulations with a structure-based protein model developed based on the energy landscape theory. We showed that the heme binding increases the stability of the myoglobin. More importantly, the heme binding tends to increase the protein folding cooperativity, and switch the folding process from a “three-state” mechanism to a “two-state” mechanism. We also showed that the folding pathways of the myoglobin can be modulated by the heme binding. By performing comparative simulations, we revealed that the above effects of heme binding are resulted from the heme induced folding of F-helix, which is otherwise unstructured at apo state, and the heme mediated contacting interactions around the heme binding site. The simulation results are consistent with available experimental data, and provide insights into the molecular mechanism of the effects of cofactor binding on the protein folding and stability.
Energy Landscape Modeling of Escape Time Distributions Reveals the Molecular Mechanism of α-Synuclein Translocation through a VDAC Nanopore
