Biophysical Society Thematic Meeting | Hamburg 2022

Biophysics at the Dawn of Exascale Computers

Poster Abstracts

54-POS Board 54 MOLECULAR DYNAMICS SIMULATIONS STUDY OF ATP BINDING IN ACETYLATED CDK1 Krishna K Vishwakarma 1 ; Ullas K Seetharaman 2 ; Ravindra Venkatramani 1 ; 1 TIFR Mumbai, Department of Chemical Science, Mumbai, India 2 TIFR Mumbai, Department of Biological Science, Mumbai, India 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. However, previous studies on kinases by others as well as on CDK1 by our group have suggested that acetylation may not impact ATP binding. Here using multiple long all atom molecular dynamics (MD) simulations (a total time of 20 μs) combined with structural, dynamic, and binding free energy analysis, we examine the underlying molecular mechanisms by which CDK1 preserves ATP binding despite the loss of the positive charge at the K33 site. Our results show that the loss in the enthalpic contribution to free energy of ATP binding upon acetylation or acetyl-mimic mutation (K33Q) is compensated by a gain of entropic contributions. Rather surprisingly, the entropic stabilization does not appear to be only localized at the active site but also at distant loop regions away from the active site. We will discuss the implications of these long-range effects on the functional activation of CDK1.

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