What make malarial adenosine deaminase from PLASMODIUM VIVAX recognise adenosine and 5'-methylthioadenosine: simulation studies.

Malaria is a life-threatening disease in humans caused by Plasmodium parasites. Plasmodium vivax (P. vivax) is one of the prevalent species found worldwide. An increase in an anti-malarial drug resistance suggests the urgent need for new drugs. Zn2+-containing adenosine deaminase (ADA) is a promising drug target because the ADA inhibition is fatal to the parasite. Malarial ADA accepts both adenosine (ADN) and 5'-methylthioadenosine (MTA) as substrates. The understanding of the substrate binding becomes crucial for an anti-malarial drug development. In this work, ADA from P. vivax (pvADA) is of interest due to its prevalence worldwide. The binding of ADN and MTA are studied here using Molecular Dynamics (MD) simulations. Upon binding, the open and closed states of pvADA are captured. The displacement of α7, linking loops of β3/α12, β4/α13, β5/α15, and α10/α11 is involved in the cavity closure and opening. Also, the inappropriate substrate orientation induces a failure in a complete cavity closure. Interactions with D46, D172, S280, D310, and D311 are important for ADN binding, whereas only hydrogen bonds with D172 and D311 are sufficient to anchor MTA inside the pocket. No Zn2+-coordinated histidine residues is acquired for substrate binding. D172 is found to play a role in ribose moiety recognition, while D311 is crucial for trapping the amine group of an adenine ring towards the Zn2+ site. Comparing between ADN and MTA, the additional interaction between D310 and an amine nitrogen on ADN supports a tighter fit that may facilitate the deamination.Communicated by Ramaswamy H. Sarma.