Albany 2013: Book of Abstracts
June 11-15 2013
©Adenine Press (2012)
Role of Conserved water molecular triad in the recognition of IMP, NAD+ with Asp 274, Asn 303, Arg 322 and Asp 364 in both the isoform of hIMPDH
IMPDH (Inosine monophosphate dehydrogenase) plays an important role in the GMP (Guanosine monophosphate) biosynthesis pathway. As hIMPDH-II is involved in CML-Cancer, so it is thought to be an active target for leukemic drug design. The importance of conserved water molecules in the salt-bridge mediated interdomain recognition and loop-flap recognition of hIMPDH have already been indicated in some simulation studies (Mishra et al. 2012, Bairagya et al. 2012, Bairagya et al. 2011a,2011b, Bairagya et al. 2009). In this work, role of conserved water molecules in the recognition of IMP ( Inosine monophosphate ) and NAD+ ( co-factor ) to active site residues of both the isoforms have been investigated by all atoms MD-Simulation studies. During 25 ns Dynamics of the solvated hIMPDH-II and I (1B3O and 1JCN PDB structures), the involvement of conserved water molecular triad (WM, WL and WC) in the recognition of active site residues (Asp 274, Asn 303, Arg 322 and Asp 364), IMP and NAD+ have been observed (Fig.1). The H-bonding co-ordination of all three conserved water molecular centers are within 4-7 and their occupation frequency is 1.0. The H-bonding geometry and the electronic consequences of the water molecular interaction at the different residues ( and also IMP and NAD+) may put forward some rational clues on antileukemic agent design.
This research has been supported by Department of Biotechnology, Govt. of India.
H.R. Bairagya, H.R., & Mukhopadhyay, B.P. (2012). An insight to the dynamics of conserved water-mediated salt bridge interaction and interdomain recognition in hIMPDH isoforms. Journal of Bimolecular Structure and Dynamics, DOI:10.1080/07391102.2012.712458.
H.R. Bairagya, H.R., Mukhopadhyay, B.P., & Bera, A.K. (2011a). Role of salt bridge dynamics in inter domain recognition of human IMPDH isoforms: an insight to inhibitor topology for isoform-II. Journal of Bimolecular Structure and Dynamics, 29(3), 441-462.
H.R. Bairagya, H.R., Mukhopadhyay, B.P., & Bera, A.K. (2011b). Conserved water mediated recognition and the dynamics of active site Cys 331 and Tyr 411 in hydrated structure of human IMPDH-II. Journal of Molecular Recognition, 24, 35 – 44.
H.R. Bairagya, H.R., Mukhopadhyay, B.P., & Sekar K. (2009). An insight to the dynamics of conserved water molecular triad in IMPDH II (human): recognition of cofactor and substrate to catalytic Arg 322. Journal of Bimolecular Structure and Dynamics, 27, 149–158.
Deepak K. Mishra
Department of Chemistry