molecular dynamics simulation of phosphorylated kid post-translational modification分子动力学模拟的磷酸化孩子翻译修饰.pdfVIP

Molecular Dynamics Simulation of Phosphorylated KID Post-Translational Modification Hai-Feng Chen1,2* 1 College of Life Sciences and Biotechnology, Shanghai Jiaotong University, Shanghai, China, 2 Shanghai Center for Bioinformation Technology, Shanghai, China Abstract Background: Kinase-inducible domain (KID) as transcriptional activator can stimulate target gene expression in signal transduction by associating with KID interacting domain (KIX). NMR spectra suggest that apo-KID is an unstructured protein. After post-translational modification by phosphorylation, KID undergoes a transition from disordered to well folded protein upon binding to KIX. However, the mechanism of folding coupled to binding is poorly understood. Methodology: To get an insight into the mechanism, we have performed ten trajectories of explicit-solvent molecular dynamics (MD) for both bound and apo phosphorylated KID (pKID). Ten MD simulations are sufficient to capture the average properties in the protein folding and unfolding. Conclusions: Room-temperature MD simulations suggest that pKID becomes more rigid and stable upon the KIX-binding. Kinetic analysis of high-temperature MD simulations shows that bound pKID and apo-pKID unfold via a three-state and a two-state process, respectively. Both kinetics and free energy landscape analyses indicate that bound pKID folds in the order of KIX access, initiation of pKID tertiary folding, folding of helix a , folding of helix a , completion of pKID tertiary folding, B A and finalization of pKID-KIX binding. Our data show that the folding pathways of apo-pKID are different from the bound state: the foldings of helices aA and aB are swapped. Here we also show that Asn139, Asp140 and Leu141 with large W-