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Molecular dynamics simulation of SKG132: An initiation to understand the mechanism of plasminogen activation 


MOJ Proteomics & Bioinformatics
Faegheh Kazemi,1,2 Seyed Shahriar Arab,3 Farzin Roohvand,1 Nasir Mohajel,1 Malihe Keramati,4 Niloofar Niknam,3 Saeed Mortezazadeh3

Abstract

To gain insights into the high plasminogen (Pg) activation of SKG132 from group G (SKG) streptococci, molecular dynamics (MD) simulation was carried out for both standard SK from group C (SKC) and SKG132 with four natural residual substitutions (Ile33Phe, Arg45Gln, Asn228Lys, Phe287Ile). The aim of this study was to examine the structural alterations induced by mentioned substitutions in SKG132. Structural analysis of MD simulation results showed two regions with increased flexibility; residues 156-161 and 183-187 which structurally located around 250 loop(251-264). In addition, residues 301- 372 showed decreased flexibility in SK╬│ of SKG132. Presence of enhanced flexible region around functionally important 250 loop and also formation a stable SK.Pg complex due to decreased flexibility of 301-372 region, may lead to improve substrate processing and high Pg activation of SKG132. Moreover, results of protein interaction calculators (PIC), showed presence of hydrogen bond in residue pairs of Lys256-Lys183, Lys256-Glu272 and Lys257-Glu272 in SKC, while they were disrupted in SKG132 and led to formation of three unbinding crucial residues including Lys256, Lys257 and Glu272. Therefore, it is concluded that better exposure of 250 loop for substrate, presence of three unbinding critical residues (Lys256, Lys257 and Glu272) and formation of a stable complex, probably play important roles in increased Pg activation of SKG132 by participating in effective interactions with substrate plasminogen. These results showed the structural differences between SKG132 and SKC in atomic details. The results may be further used for design of SK drug with altered conformation and enhanced activity.

Keywords

streptokinase, molecular dynamics simulations, structural dynamics, streptokinase activity

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