Molecular dynamics simulations reveal that acetylation of catalytic lysine balances enthalpic destabilization with entropic stabilization to preserve ATP binding affinities in CDK1

Abstract

The cyclin-dependent kinase 1 (CDK1) is an essential enzyme that controls cell cycle progression from the G2 to M phase. The molecular function of CDK1 is to transfer a gamma phosphate from ATP to the target protein substrate. While several factors regulate the activity of CDK1, the role of acetylation, a post-translational modification (PTM), at catalytic lysine (K33) located in the active site pocket is less understood. Acetylation removes the positive charge of K33 which serves as an anchor to negatively charged ATP molecules and is thus intuitively expected to lower ATP binding affinity.