Structure, dynamics and solvation of HIV-1 protease/saquinavir complex in aqueous solution and their contributions to drug resistance: molecular dynamic simulations. 
As it is known that the understanding of the basic properties of the enzyme/inhibitor complex leads directly to enhancing the capability in drug designing and drug discovery.  Molecular dynamics simulations have been performed to examine detailed information on the structure and dynamical properties of the HIV-1 PR complexed with saquinavir in the three protonated states, monoprotonates at Asp25 (Mono-25) and Asp25'(Mono-25') and diprotonate (Di-Pro) at both Asp25 and Asp25'.  The obtained results support clinical data which reveal that Ile84 and Gly48 are two of the most frequent residues where mutation toward a protease inhibitor takes place.  In contrast to the Ile84 mutation due to high displacement of Ile84 in the presence of saquinavir, source of the Gly48 mutation was observed to be due to the limited space in the HIV-1 PR pocket.  The Gly48 was, on one side, found to form strong hydrogen bonds with saquinavir, while on the other side this residue was repelled by the hydrophobic Phe53 residue.  In terms of inhibitor/enzyme binding, interactions between saquinavir and a catalytic triad of the HIV-1 PR were calculated using the ab initio method.  The results show an order of the binding energy of Mono25<Di-pro<<Mono-25', suggesting that the active site in the HIV-1 PR complexed with saquinavir is monoprotonated states on Asp25.  In contrast to the binding energy, 3, 6 and 12 hydrogen bonds between saquinavir and HIV-1 PR were found for the Mono-25, Mono-25' and Di-pro states, respectively.  Discrepancy between the two trends suggests us to conclude that interaction between inhibitor and catalytic residues should be used as a criteria to enhance capability in drug designing and drug screening instead of using the total inhibitor/enzyme interaction which is normally reported in the literature.  In addition, the distribution and binding of water molecules, in terms of hydrogen bonding, to the donor atoms of saquinavir were investigated and discussed, referring to that which was reported experimentally.