According to the recent report on malaria [1] , the death of thousands of children is alarming. It is known that malaria is caused mainly by Plasmodium vivax, Plasmodium falciparum and Plasmodium malariae, transmitted through female Anopheles mosquito [2] .

Historical developments [3] -[5] in the treatment of malaria started from extraction of quinine from the bark of cinchona in the year 1820.

Derivatives of Quinine like Amodiaquine, Mefloquine, Primaquine [5] are still used in the prevention and treatment of malaria. This class of drug acts [6] -[8] on the food vacuoles of the parasites. Parasites obtain amino acids for protein translation and formation of their cell membrane from digestion of hemoglobin in the host. The undigested free toxic heme groups, form reactive oxygen species. The natural process of removing this toxic heme group from the parasitic cell is by the process of bio crystallization of heme to haemozoin [9] . The chloro-quinine inhibits this process of removal of toxic heme groups from parasitic cells and thus kills parasites.

Artemisinin [10] is a redox drug. In metabolic processes, reactive oxygen intermediates are produced as redox wastes. Those can damage the cell components. However, cells have their own mechanism of preventing the formation of redox wastes [11] . The artemisinin-type drug accelerates the formation of these redox wastes in parasites causing parasitic cell death.

Sulfa drugs inhibit activities of two enzymes needed for the folate synthesis [12] ; the parasites grow rapidly using nucleic acids synthesized by protein folate [13] . Thus, these drugs suppress parasitic growth.

Atovaquone [14] (Figure 1), is a modern generation drug that acts as the ubiquone (Figure 2) inhibitor in the mechanism of the mitochondrial respiration [15] of the parasitic cells.

The mitochondrial electron transfer (Figure 3) occurs through several consecutive redox reactions as schematically shown below.

The quinine group of ubiquone gets reduced to the quinol and helps in transferring the electron through an oxidation-reduction cycle [16] [17] . Atovaquone too has a quinine group and thus, it can mimic ubiquone and binds selectively to the Q₀ site of parasitic mitochondria thereby block the parasitic mitochondrial respiration [14] .

In the present study, we report binding characteristics of trans- and cis-isomers of Atovaquone with cytochrome bc1 of yeast using docking technique in order to address the basic question, why cis-Atovaquone is not an anti-malarial drug? We have carried out the computation with cytochrome bc1 of yeast as experimental crystallographic data of Atovaquone-bound mitochondrial cyt bc1 of yeast are available in a very recent literature [18] report.

Recently, Hunte et al. reported [18] [19] crystal structure analysis of Atovaquone-bound cytochrome be1 complex of yeast and discussed [19] [20] elaborately different binding features of the drug molecule but it was limited to trans-Atovaquone only. Despite several studies, the molecular mechanism of ubiquinol oxidation is not yet clearly known. The mechanism of bifurcated electron transfer paths involves transport of one electron via the 2Fe-2S path of Rieske protein, and the other electron is transported via b-type heme. The-NH centre of His-181 of Rieske protein plays an important role [18] in such electron transport process. Thus, if this centre is blocked by an H-bond with the drug molecule, it will interrupt the normal mitochondrial electron transport process.

Unlike our previous model [21] , we have excluded here H₂O assisted H-bonding interaction between Glu272 and Atovaquone, as this interaction is absent in the experimentally determined crystal structure [18] of Atovaquone bound cytbc1.

In the present computation method, simulated annealing [21] [22] process of docking was adopted. The drug molecule (ligand) was considered flexible in terms of its translational orientation and conformational changes. The Auto Dock software (3.0) calculated the local energy minima for different configurations of the drug molecule at the binding site of cytochrome bc1 to obtain the global minimum structure. Monte Carlo simulated annealing technique [23] was used for configuration exploration. The energy calculation was done by the grid based affinity potential [24] . Auto Dock version 3.0 employed local search method based on the optimization of algorithm of Solis and Wets (SW) [25] and global search method by genetic algorithm (GA).

In this approach, the input parameters like atomic coordinates for the cytochrome bc1 was taken from protein data bank and represented “extended” atom representation where the amino, hydroxyl, methyl groups are treated as the single entity. Thus, a single extended amino group replaces four real atoms to reduce the time of computation. The calculation of the energy at different points was obtained by the grid calculation with the drug molecule kept at different grid points. The energy at a grid point was calculated on the basis of affinity potential using the classical Lenard Jones potential and electrostatic potential calculated by considering the atoms as point charges of +1 using a Poison-Boltzmann finite difference method [26] . After calculating the energy at the eight grid points surrounding any atom, an average energy was obtained. The total energy was calculated considering three main interactions 1) Lenard Jones interaction; 2) Electro static interaction; 3) The hydrogen bonding interaction. It may be mentioned here that the novelty of this computation is that coordinates of the drug molecules were obtained from experimentally determined crystal structures of these molecules. The cytochrome bc1 protein orthogonal crystal coordinates were obtained by deleting Stigmatellin coordinates from reported Stigmatellin + cytochrome bc1 protein crystal (PDB code-1EZV) coordinates. The combination of the orthogonal coordinates of the Atovaquone with those of the protein [27] was done by the software win Coot version 0.3.3 [27] . The PyMOL windows version 0.99 was used for viewing and drawing the energy minimized structure of Atovaquone bound cytochrome bc1 complexes.

In the present research, we have presented for the first time the energy minimized binding pattern of cis-Ato- vaquone (which is not an anti-malaria drug) with cytochrome bc1of yeast using simple molecular docking calculation and compared with similar binding pattern of the drug molecule, trans-Atovaquone. We have hypothesized H-bonding interaction between −NH of His181 of Rieske protein and C=O of Atovaquone plays a crucial role in dictating drug potency of Atovaquone.

SBM is thankful to Dr. Sekhar of IISc, Bangalore for his valuable suggestions and guidance.

SrijitaBasumallick,T. N. GuruRow, (2015) Binding Study of Cis-Atovaquone with Cytochrome bc1 of Yeast. Computational Molecular Bioscience,05,57-63. doi: 10.4236/cmb.2015.54007