Variability of the Cyclin-Dependent Kinase 2 Flexibility Without Significant Change in the Initial Conformation of the Protein or Its Environment; a Computational Study

Abstract

Protein flexibility probably is a phenomenon that can make the existence of the many protein conformations possible in contrast to a limited number. Many conformations in a protein are needed for doing many functions. For instance, based on searching IntAct PPI database with the UniprotKB accession number of hCDK2: P24941, hCDK2 has at least 200 different interactions with other proteins in addition to interactions by itself (1). As a structural characteristic, protein flexibility plays many functional roles with respect to different aspects of the proteins as well. Examples in this regard are enzyme catalysis and ligand-receptor interactions, substrate and ligand orientation, the turnover rate of the substrates, and reduction of the free energy barrier in the active sites (2).In structural bioinformatics tools, there are many instances regarding protein flexibility applications and usefulness; as an example, improvement of the small ligand-receptor docking (3,4 Background: Protein flexibility, which has been referred as a dynamic behavior has various roles in proteins' functions. Furthermore, for some developed tools in bioinformatics, such as protein-protein docking software, considering the protein flexibility, causes a higher degree of accuracy. Through undertaking the present work, we have accomplished the quantification plus analysis of the variations in the human Cyclin Dependent Kinase 2 (hCDK2) protein flexibility without affecting a significant change in its initial environment or the protein per se. Objectives:The main goal of the present research was to calculate variations in the flexibility for each residue of the hCDK2, analysis of their flexibility variations through clustering, and to investigate the functional aspects of the residues with high flexibility variations. Materials and Methods: Using Gromacs package (version 4.5.4), three independent molecular dynamics (MD) simulations of the hCDK2 protein (PDB ID: 1HCL) was accomplished with no significant changes in their initial environments, structures, or conformations, followed by Root Mean Square Fluctuations (RMSF) calculation of these MD trajectories. The amount of variations in these three curves of RMSF was calculated using two formulas.Results: More than 50% of the variation in the flexibility (the distance between the maximum and the minimum amount of the RMSF) was found at the region of Val-154. As well, there are other major flexibility fluctuations in other residues. These residues were mostly positioned in the vicinity of the functional residues. The subsequent works were done, as followed by clustering all hCDK2 residues into four groups considering the amount of their variability with respect to flexibility and their position in the RMSF curves. Conclusions:This work has introduced a new class of flexibility aspect of the proteins' residues. It could also help designing and engineering proteins, with introducing a new dynamic aspect of hCDK2, and accordingly, for the other similar globular proteins. In addition, it could provide a...