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

Abstract

Calcineurin (CaN) is a eukaryotic serine/threonine protein phosphatase activated by both Ca²⁺ and calmodulin (CaM), including intrinsically disordered region (IDR). The region undergoes folding into an α-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 Å.

Keywords: free-energy analysis; intrinsically disordered protein; molecular dynamics simulation; multi-scale method.