Abstract
The Ran GTPase protein is a guanine nucleotide-binding protein (GNBP) with an acknowledged profile in cancer onset, progression and metastases. The complex mechanism adopted by GNBPs in exchanging GDP for GTP is an intriguing process and crucial for Ran viability. The successful completion of the process is a fundamental aspect of propagating downstream signalling events. QM/MM molecular dynamics simulations were employed in this study to provide a deeper mechanistic understanding of the initiation of nucleotide exchange in Ran. Results indicate significant disruption of the metal-binding site upon interaction with RCC1 (the Ran guanine nucleotide exchange factor), overall culminating in the prominent shift of the divalent magnesium ion. The observed ion drifting is reasoned to occur as a consequence of the complex formation between Ran and RCC1 and is postulated to be a critical factor in the exchange process adopted by Ran. This is the first report to observe and detail such intricate dynamics for a protein in Ras superfamily.
Highlights
Ran GTPase (Ran) is a small, 24 kDa eukaryotic protein belonging to the Ras superfamily of small G-proteins [1]
This study reports the first hybrid QM/MM molecular dynamics simulation targeted at identifying aspects relating to the nucleotide exchange of Ran
It can be seen that the complex system evolves to an RMSD of approximately 2 Å in the first 15 ns of simulation and stabilizes, except that a sharp fluctuation in alpha carbon RMSD was observed towards the end of the production simulation. This fluctuation may correspond to conformational rearrangements of the complex system
Summary
Ran GTPase (Ran) is a small, 24 kDa eukaryotic protein belonging to the Ras superfamily of small G-proteins [1]. It exerts its function in many aspects of cellular activity [2]. Ran is implicated in other cellular events including spindle assembly, coordination of DNA synthesis and nuclear envelope reformation. Ran is highly over-expressed in various cancer cells such as epithelial ovarian cancer and pancreatic cancer [3, 4]. El-Tanani et al suggested that mutation of Ran is associated with activation of PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways and is a potential target for treatment of cancers [6]
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