QM/MM Study For The Function Of Crystal Water In The Binding Between HIV-1 Protease And Ligand

More and more attentions have been paid into the research of macro-biological molecules molecular dynamics (MD), as more and more interests has been paid to practical application. The current computational technology has made that computational molecular simulation plays a very important and activity foreland task in chemistry, biochemistry, molecular biology. MD simulation can provide the detail information of macro-biological molecules based on the atomic pairwise interaction. The absolute free energy calculation based on the MD simulation plays a very important role in the molecular recognition based on MD. The sign of free energy describes the orientation of chemistry reaction, the magnitude of free energy determines the tendency. MD simulation plays a very important role in the relationship of macro-biological molecules structure and function.HIV-1 protease (PR) is one of the primary targets for drug development against HIV-1 infection due to its key role in viral maturation. The active site region is covered by two flaps, which can interact with inhibitors directly through a special water molecule W301. The special water molecule W301 which bridges the flaps of PR and ABT-538 is observed to participate in hydrogen-bonding interactions between the flaps and the ABT-538. We investigate the configuration change of HIV-1 PR under the effect of W301,and present a QM/MM calculation of binding free energy between W301 and PR/ABT-538 to investigate the detailed interaction strength between the bridge water W301 and PR/ABT-538 complex.The protonation state of the catalytic aspartic acids in the HIV-1 PR was not determined by a specific experimental study. According to the commonly accepted mechanism of the protease reaction, only one of the catalytic aspartic acid residues in the HIV-1 PR active site should be protonated, while the other one exists as the anion. Examination of the hydrogen bonding networks in the HIV-1 PR/ABT-538 complex, which included the catalytic aspartic acids, suggested that the single site of protonation was either the OD2 of the Asp25 (A chain) or OD2 of the Asp25 (B chain). Hence, when we studied the contribution of W301 in the binding free energies between PR and ABT-538, we carried out the QM/MM MD simulation of the complex in two alternative monoprotonation states: protonated at the OD2 of Asp25(B chain) denoted as (-1,0) or protonated at the OD2 of Asp25(A chain) denoted as (0,-1). PR is at (-1, 0) state calculated at PM3 level, the binding free energy of W301 to PR/ABT-538 is -13.54 kJ/mol. The binding free energy of W301 to PR/ABT-538 is -23.99 kJ/mol, when PR is at (0,-1) state calculated at the level of PM3.Four examples of the B-Factor values of each residue derived from the 1-ns QM/MM MD trajectories at the level of AM1 and PM3 have been calculated. the flexibility of residues of PR is reduced after the invasion of W301 at the monoprotonation state (-1,0), while flexibility of residues of PR increases after the invasion of W301 at the monoprotonation state (0,-1). We calculate the molecular electrostatic potential (MEP) of ABT-538 using Gaussian 03 based on the idea of quantitative structure-activity relationships (QSAR). We can observe a much more intense region of negative electrostatic potential around the O2 and O4 atoms. This observation can be related with the hydrogen bonds formed between W301 and ABT-538.It is showed that W301 has a critical effect on the stability of PR at two monoprotonation states. W301 plays a very important role in the binding between HIV-1 PR and ABT-538.