Study of HIV-1 Protease Mutants Using Molecular Dynamics in a Grid Based Computational Plataform

For the AIDS virus to mature, HIV protease must process the viral polyproteins gag and gag-pol specifically at nine non-homologous sites [1]. The protease has been a prime target in the massive structure-based drug design effort to combat AIDS, since it is essential to viral maturation. The inhibition of HIVs protease has been reaching success on clinical treatments. However, the fast emergency of drugs resistance by the virus is a difficult problem to be resolved. Different HIV strains that display resistance have been appearing according to the region of the planet. For example, in south Brazil there are resistant mutants that owns different amino acid sequences, related to other parts of the country. Moreover, a World Health Organization’s forecast states that around ninety percent of infected people by the virus, at this beginning of XXI century, will belong to developing nations. So, it is necessary to increase both theoretical and experimental efforts that enable the development of new drugs against regional mutants. Recent work presents Brazilian HIV-1 mutant analysis [2]. Our goal is to further develop this work making HIV protease mutants, by replacing aminoacid residues by alanine in order to evaluate the residue weight interaction with the substratum and with the inhibitors. A mapping of the main residues and of their role in the structure and in the protease dynamics, as well as their participation in the activity of the enzyme, can help drugs development in a short period of time. The accomplishment of such experimental study is difficult, it involves great demand of time and resources. For instance, the Molecular Dynamics (MD) simulation of several protease-inhibitor complex using the Molecular Dynamic Simulation tools THOR [3] is a feasible task. In order to decrease the total time spent in the research we are using computational grids, wich can be defined as large number of heterogeneous machines distributed over a vast geographic area. In a recent work [4] we have got successful results running Thor dynamic simulation tasks over 60 machines grid environment, based on a grid framework MyGrid [5]. In this work we evaluate the amino acid contacts in the dimer interface at HIV-1 protease complexed with 1 inhibitor. It is applied dynamic simulation using Thor simulation tool over Mygrid computing environment. Our goal is a better understanding of the HIV-1 protease dimer contact region and its role in the HIV drug-resistence mechanism. Also, we expect contributing to increase Molecular Dynamic research in Grid environment.