Molecular Dynamics Study on Function of 2-ylacetic acid-Benzothiophene in Binding of HIV-1 Protease and Inhibitor
Received date: 2013-03-25
Online published: 2013-05-24
Supported by
Project supported by the Natural Science Foundation of Shandong Province (No. ZR2011HM048) and the National Natural Science Foundation of China (No. 11274206).
In order to study the role of allosteric fragment 2-ylacetic acid-benzothiophene (2FX) in the binding of HIV-1 protease (PR) and inhibitor, the molecular dynamics simulations of 100 nanoseconds have been successfully performed on two systems of HIV-1 protease and inhibitor, respectively, one of which 2FX is attached to and another is not. Both types of new force fields, ff99SBildn and ff12SB, and GPU parallel computing technology have been used for each of the two systems in the simulations. By investigating the influence of 2FX on the protease, it is found that the binding of 2FX induces a conformational change of the protease. The dynamics behaviors of the two systems under the two force fields are compared with the VMD visualization software and it is found that, to a certain extent, there exist differences between those from the different forces. The root-mean-square deviations (RMSD), the B-factors of the two systems, and structure superposition between the calculated and X-ray crystal structures, which display that the system with 2FX has a more stable dynamics process and the vibration extent of the residues decreases, indicate that the 2FX bound in the protease can stabilize the system. The binding free energies have been calculated using the two force fields and using two methods, MM-PB/GBSA, respectively. The resulting free energy values, ff99SBildn: -70.52 and -68.42 kcal/mol (PB), -86.72 and -89.40 kcal/mol (GB); ff12SB: -75.40 and -77.68 kcal/mol (PB), -87.01 and -93.75 kcal/mol (GB), 2FX-system being generally of greater magnitudes, also suggest the allosteric fragment stabilizes the binding of inhibitor and PR. The present results, despite the discrepancies between those from the two different force fields, demonstrate that the allosteric fragment 2FX unambiguously gives rise to subtle changes of structure of the PR and make the inhibitor and PR combine more firmly. In particular, it is clear that the fragment acts to weaken the flexibility of the flap, strengthening the combination of the inhibitor and PR. In addition, it is also found that, with ff12SB force field, the dynamics processes are more stable, the calculated binding free energies are more favorable, and the results are better consistent with the experiments than with ff99SBildn. It is expected that this work could be helpful to design new allosteric inhibitors in the future.
Meng Xianmei , Wang Jialei , Zhang Shaolong , Zhang Qinggang . Molecular Dynamics Study on Function of 2-ylacetic acid-Benzothiophene in Binding of HIV-1 Protease and Inhibitor[J]. Acta Chimica Sinica, 2013 , 71(08) : 1167 -1174 . DOI: 10.6023/A13030327
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