Role of carbon in crystal structures of wild-type and mutated form of dihydrofolate reductase-thymidylate synthase of plasmodium falciparum.

ABSTRACT

Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) is an important target of antimalarial drugs. A characteristic set of mutations in this bifunctional enzymatic protein leads to reduced competitive drug binding at the enzyme's active site. The carbon content distribution study at mutational sites and along the amino acid sequence of this important protein was carried out using carbon analysis tool CARBANA. The mutational sites at residues 16, 51, 59, 108, and 164 were investigated. The study reveals that the carbon content and distribution of A16V and S108N mutants is shifting towards a normal distribution of the carbon content which is symmetrical about 0.3145, conforming to the value for stable and ordered protein. The study also reveals that carbon distribution of PfDHFR-TS mutant protein is maintained at 31.45% of carbon all along the sequence. The hydrophobicity of the entire sequences also balances quite well at the optimum position and carbon is the only element contributing towards this stability. Thus, the study of carbon distribution in mutations of PfDHFR-TS is the most significant step towards understanding the biological features which can provide possible approaches for the design of new drugs to overcome antifolate resistance.