600 ps molecular dynamics reveals stable substructures and flexible hinge points in cAMP dependent protein kinase

Molecular dynamics simulations of the catalytic subunit of cAMP dependent p rotein kinase (cAPK) have been performed in an aqueous environment. The rel ations among the protein hydrogen-bonding network, secondary structural ele ments, and the internal motions of rigid domains were examined. The values of fluctuations of protein dihedral angles during dynamics show quite disti nct maxima in the regions of loops and minima in the regions of alpha-helic es and beta-strands. Analyses of conformation snapshots throughout the run show stable subdomains and indicate that these rigid domains are constraine d during the dynamics by a stable network of hydrogen bonds. The most stabl e subdomain during the dynamics was in the small lobe including part of the carboxy-terminal tail. The most significant flexible region was the highly conserved glycine-rich loop between beta strands 1 and 2 in the small lobe . Many of the main chain dihedral angle changes measured in a comparison of the crystallographic structures of "open" and "closed" conformations of aA PK correspond to the highly flexible residues found during dynamics. (C) 19 99 John Wiley & Sons, Inc.