Atomistic detailed free-energy landscape of intrinsically disordered protein studied by multi-scale divide-and-conquer molecular dynamics simulation

Calcineurin (CaN) is a eukaryotic serine/threonine protein phosphatase activated by both Ca(2+)and calmodulin (CaM), including intrinsically disordered region (IDR). The region undergoes folding into an alpha-helix form in the presence Ca2+-loaded CaM. To sample the ordered structure of the IDR by conventional all atom model (AAM) molecular dynamics (MD) simulation, the IDR and Ca2+-loaded CaM must be simultaneously treated. However, it is time-consuming task because the coupled folding and binding should include repeated binding and dissociation. Then, in this study, we propose novel multi-scale divide-and-conquer MD (MSDC-MD), which combines AAM-MD and coarse-grained model MD (CGM-MD). To speed up the conformation sampling, MSDC-MD simulation first treats the IDR by CGM to sample conformations from wide conformation space; then, multiple AAM-MD in a limited area is initiated using the resultant CGM conformation, which is reconstructed by homology modeling method. To investigate performance, we sampled the ordered conformation of the IDR using MSDC-MD; the root-mean-square distance (RMSD) with respect to the experimental structure was 2.23 angstrom.

Automated summary

In this study, a novel multi-scale divide-and-conquer MD (MSDC-MD) method was proposed to speed up the conformation sampling of the intrinsically disordered region (IDR) of calcineurin. By combining all atom model (AAM) molecular dynamics (MD) with coarse-grained model MD (CGM-MD), the MSDC-MD approach first samples wide conformation space using CGM before initiating multiple AAM-MD simulations in a limited area. The performance was evaluated by sampling the ordered conformation of the IDR, resulting in a root-mean-square distance (RMSD) of 2.23 angstrom with respect to the experimental structure.