Structural basis for decreased affinity of Emodin binding to Val66-mutated human CK2 alpha as determined by molecular dynamics
Protein kinase CK2 (casein kinase 2) is a multifunctional serine/threonine kinase that is involved in a broad range of physiological events. The decreased affinity of Emodin binding to human CK2 alpha resulting from single-point mutation of Val66 to Ala (V66A) has been demonstrated by experimental mutagenesis. Molecular dynamics (MD) simulations and energy analysis were performed on wild type (WT) and V66A mutant CK2 alpha-Emodin complexes to investigate the subtle influences of amino acid replacement on the structure of the complex. The structure of CK2 alpha and the orientation of Emodin undergo changes to different degrees in V66A mutant. The affected positions in CK2 alpha are mainly distributed over the glycine-rich loop (G-loop), the alpha-helix and the loop located at the portion between G-loop and alpha-helix (C-loop). Based on the coupling among these segments, an allosteric mechanism among the C-loop, the G-loop and the deviated Emodin is proposed. Additionally, an estimated energy calculation and residue-based energy decomposition also indicate the lower instability of V66A mutant in contrast to WT, as well as the unfavorable energetic influences on critical residue contributions.
emodin protein kinase ck2 binding affinity hydrophobic interaction mm/pbsa molecular dynamics simulations