Structural bioinformatics insights into ATP binding mechanism in zebrafish (Danio rerio) cyclin‐dependent kinase‐like 5 (zCDKL5) protein

Abstract

In mammalian systems, the conserved cyclin-dependent protein kinases (CDKs) control the process of cell division and curb the transcription mechanism in response to diverse signaling events that are essential for the catalytic activity. In zebrafish, zCDKL5 portrays differential expression profiling in several tissues and presumed to play a vital role in the neuronal development. In this present study, the sequence-structure relationship and mode of ATP binding in zCDKL5 was unveiled through theoretical modeling, molecular docking, and MD simulations. Like human CDKs, the modeled zCDKL5 was found to be bipartite in nature, where, ATP binds to the central cavity of the catalytic domain through a strong network of H-bonding, electrostatic, and hydrophobic interactions. MD simulation portrayed that conserved residues, viz, Ile10, Gly11, Glu12, Val18, Val64, Glu81, Cys143, and Asp144 were indispensable for tight anchoring of ATP and contribute to the stability of the zCDKL5-ATP complex. MM/PBSA binding free energy analysis displayed that van der Waal energy (ΔG vwd ) and Electrostatic energy (ΔG ele ) were the major contributors towards the overall binding free energy. Thus, the comparative structural bioinformatics approach has shed new insights into the dynamics and ATP binding mechanism of zCDKL5. The results from the study will help to undertake further research on the role of phosphorylated CDKL5 in the onset of neurodevelopmental disorders caused by mutations in higher eukaryotic systems. K E Y W O R D S cyclin-dependent protein kinases, MD simulation, molecular docking, principal component analysis, zebrafish

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“…It is often seen that in the absence of a experimentally derived protein structure, comparative modeling of the protein accurately generates suitable 3D models for a wide spectrum of applications. 51,54 It is usually a method of choice where a relationship of homology between the sequence of a target protein and at least one known structure is found. A high level of sequence identity promises a more reliable alignment between the target sequence and the template structure.…”

“…To understand the global motion of each system during the dynamics condition, principal component analysis (PCA) of the CARD complexes was carried out using gmx covar and gmx anaeig tools. [47][48][49][50][51][52] The 2D plots depicting the dynamic stabilities of each system were generated using the Grace 5.1.23 program.…”

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