The dimeric structures of the Lys49 phospholipase A2, a comparative study by molecular dynamic.
Lourenzoni, M. R.(1); Murakami, M. T. (2); Degrève, L(1); Arni, R. K.(2)
1Departamento de Química, FFCLRP, USP, Ribeirão Preto-SP, Brazil; 2Departamento de Física, IBILCE, UNESP, São José do Preto-SP, Brazil.
Phospholipases A2 are abundant components of snake venom secretions and its myotoxicity is one property in a diversity of toxic and pharmacological actions, where the action modes are unknown yet. The Lys49 PLA2s are homologues and catalytically inactive but demonstrates a membrane damaging activity. The oligomeric state of the Lys49 PLA2 homologues has been accepted as important point to explain their pharmacological effects. Several crystal structures of myotoxic Lys49-PLA2s have been solved with a common dimeric conformation (extended structure). This structure is flexible and can take the "open" and "close" conformations as suggested by Ward et al that propose a "hinge" between two monomers that remain in the equilibrium conformation. Murakami et al has recently been solved the crystal structure of a Lys49 PLA2 complexed with suramin, which describes an alternative dimeric conformation (new dimer).
The molecular dynamic simulations (MD) where performed in order to obtain a better insight of two possible dimeric Lys49 PLA2 structures in aqueous solution. The Asp49 and Lys49 PLA2 monomers with suramin and only in aqueous solution were simulated too. The crystal structures were used as the initial step in MD. The results show a flexible extended structure with the relative motion of the two monomers that including the "open" and "close" conformations as suggested by Ward. The hinge was defined by presence of hydrogen bonds between monomers. The new dimer structure showed a good stability too, but with the interaction potential energy between the two monomers greater than to the extended dimer. The stability of new dimer structure is explained by hydrophobic contacts between monomers and mainly by three Cl- ions inside of a charged core. The PLA2 monomer is stable and the suramin prefer the binding with Lys49 than Asp49 PLA2 since the negative sulfonated group form a salt-bridge with group of Lys. The interaction Lys residues and trisulphonated naphthalene of the suramin could stabilize the new dimer structure. This possible interaction is agreement observations made by Murakami and enhance the importance of three Cl- ions in the stability of new dimer.
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