Preferential binding sites of waters in the HIV-1 protease pocket by quantum chemical calculations

Abstract

Role of water in the HIV-1 protease pocket, has been investigated, based on quantum chemical calculations. The interaction energies between amino acid cluster and water molecules were evaluated and compared using various methods. X-ray structure of the HIV-1 PR and of the oxygen atoms of water were taken from Protein Data Bank. The six water molecules in the crystallographic structure of the HIV-1 PR have been taken into consideration. Position of the oxygen atom of water was fixed but its orientation around the oxygen was optimized. The size of amino acid cluster was increased until consistency of the interaction energy was reached. The results show that the optimal radius of the cluster is between 5.0 and 5.5 A around water molecule accommodating 4-8 amino acid residues. The MM method, and hence the QM/MM fail to describe the investigated system while the DFT/B3LYP is the most appropriate method. Role of water molecules both in hydrolysis mechanism and in stabilizing the enzyme structure have been analyzed in terms of interaction energy and found that the calculated values for W301, W607, W566, W608, W406 and W426 are as follows; -11.49, -8.92, -11.35, -10.05, -2.88 and -8.11 kcal/mol, respectively. For W406, the interaction of -2.88 kcal/mol suggested that its role in stabilizing enzyme structure is supposed to differ from the other structural water molecules, i.e., instead of holding the enzyme by forming the hydrogen bond, it supposes to repel the residues in order to prevent them from getting collapse.