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  • Title: Molecular dynamics simulation study of valyl-tRNA synthetase with its pre- and post-transfer editing substrates.
    Author: Bharatham N, Bharatham K, Lee Y, Woo Lee K.
    Journal: Biophys Chem; 2009 Jul; 143(1-2):34-43. PubMed ID: 19398261.
    Abstract:
    The main role of aminoacyl-tRNA synthetases (aaRSs) is to transfer the cognate amino acids to the 3'-end of their tRNA by strictly discriminating from non-cognate amino acids. Some aaRSs accomplish this via proofreading and editing mechanisms, among which valyl-tRNA synthetase (ValRS) hydrolyses the non-cognate amino acid, threonine. In ValRS, existence of pre-transfer editing process is still unclear, although crystal structure of editing site with pre-transfer substrate analog (Thr-AMS) was released. In the case of isoleucyl-tRNA synthetase (IleRS), editing mechanism is well studied and mutational analyses revealed the existence of post- and pre-transfer editing mechanisms. Our aim is to investigate the possibility of pre-transfer editing process by performing molecular dynamics (MD) simulation studies. Simulations were carried out for ValRS with pre-transfer substrates (Thr-AMP/Val-AMP) and post-transfer substrates (Thr-A76/Val-A76) to understand their binding pattern. Two important point mutation studies were performed to observe their effect on editing process. This study also intends to compare and contrast the pre-transfer editing with post-transfer editing of ValRS. Interestingly, the MD simulation results revealed that non-cognate substrates (Thr-AMP/Thr-A76) bind more strongly than the cognate substrates (Val-AMP/Val-A76) in both pre- and post-transfer editing respectively. The editing site mutations (Lys270Ala and Asp279Ala) severely affected the binding ability of pre-transfer substrate (Thr-AMP) by different ways. Even though pre- and post-transfer substrates bind to the same site, specific differences were observed which has led us to believe the existence of the pre-transfer editing process in ValRS.
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