Abstract
The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method combined with molecular dynamics (MD) simulations were used to investigate the functional role of protonation in human immunodeficiency virus type 1 (HIV-1) protease complexed with the inhibitor BEA369. Our results demonstrate that protonation of two aspartic acids (Asp25/Asp25′) has a strong influence on the dynamics behavior of the complex, the binding free energy of BEA369, and inhibitor–residue interactions. Relative binding free energies calculated using the MM-PBSA method show that protonation of Asp25 results in the strongest binding of BEA369 to HIV-1 protease. Inhibitor–residue interactions computed by the theory of free energy decomposition also indicate that protonation of Asp25 has the most favorable effect on binding of BEA369. In addition, hydrogen-bond analysis based on the trajectories of the MD simulations shows that protonation of Asp25 strongly influences the water-mediated link of a conserved water molecule, Wat301. We expect that the results of this study will contribute significantly to binding calculations for BEA369, and to the design of high affinity inhibitors.
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This work is supported by the National Nature Science Foundation of China (Grant Nos. 10874104, 10474060 and 10504017), the key Project of Chinese Ministry of Education (NO.206093) and the key Project of Nature Science Foundation of Shandong Province (Z2007A05).
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Chen, J., Yang, M., Hu, G. et al. Insights into the functional role of protonation states in the HIV-1 protease-BEA369 complex: molecular dynamics simulations and free energy calculations. J Mol Model 15, 1245–1252 (2009). https://doi.org/10.1007/s00894-009-0452-y
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DOI: https://doi.org/10.1007/s00894-009-0452-y