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Acta Physico-Chimica Sinca  2016, Vol. 32 Issue (11): 2811-2818    DOI: 10.3866/PKU.WHXB201609131
Molecular Simulations on Dynamic Binding of Ibuprofen onto Site II of Human Serum Albumin: One Potential Way Analysis
Shi-Wen XU,Dong-Qiang LIN*(),Shan-Jing YAO
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Human serum albumin (HSA) has two main drug binding sites termed Site I and Site II. Most small molecules like ibuprofen (a well-known anti-inflammatory drug) bind to Site II preferentially. In this study, molecular simulation methods were used to investigate the dynamic binding process of ibuprofen to Site II. A system of 50 ibuprofen molecules distributed randomly around HSA was constructed. After a 50-ns molecular dynamics simulation, one ibuprofen molecule bound stably to Site II. Based on trajectory analysis of this ibuprofen molecule, the binding process of ibuprofen onto Site II can be divided into four phases:(i) long-range attraction; (ii) adjustment on the surface; (iii) entering to Site II pocket; and (iv) stable binding at Site II. After evaluating van der Waals' and electrostatic interaction energies during the binding process, it was found that the initial major driving force involves electrostatic attractions. Subsequently, ibuprofen locks between two polar regions on the surface near Site II and then moves to Site II. Ibuprofen then enters the pocket of Site II by combinatorial effects of polar and hydrophobic residues nearby the entrance of Site II. Electrostatic and hydrophobic interactions form the stable binding of ibuprofen in Site II. The molecular surface near Site II was observed to change significantly during binding, which indicates an induced fit mechanism. The binding mode obtained with molecular simulations is consistent with the crystal structure of the ibuprofen-HSA complex. The results show that molecular simulations would help to evaluate the dynamic binding processes of small molecules to proteins and improve our understanding of the binding mechanisms at the molecular level.

Key wordsHuman serum albumin      Site II      Ibuprofen      Dynamic binding      Molecular simulation     
Received: 25 May 2016      Published: 13 September 2016
MSC2000:  O641  
Fund:  the National Natural Science Foundation of China(21476198);the National Natural Science Foundation of China(21276228);the National Natural Science Foundation of China(21576233)
Corresponding Authors: Dong-Qiang LIN     E-mail:
Cite this article:

Shi-Wen XU,Dong-Qiang LIN,Shan-Jing YAO. Molecular Simulations on Dynamic Binding of Ibuprofen onto Site II of Human Serum Albumin: One Potential Way Analysis. Acta Physico-Chimica Sinca, 2016, 32(11): 2811-2818.

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Fig 1 HSA (a), ibuprofen (b), and the ibuprofen-HSA binding (c)
Fig 2 Distance between ibuprofen and the center of Site Ⅱ and the interaction energies of ibuprofen on to Site Ⅱ of HSA color online
Fig 3 Isopotential surface of HSA at pH 7.4 and the position of ibuprofen molecule at different simulation time The red triangle mesh represents for the electrostatic potential of -0.2kT/e, and blue for 0.2kT/e. color online
Fig 4 Comparition on the electrostatic interaction energies of two polar regions
Fig 5 Binding modes of ibuprofen on the surface of HSA at 6 ns (a) and 16 ns (b)
Fig 6 Electrostatic interaction energies of three key residues at the binding phase Ⅲ
Fig 7 Binding modes of ibuprofen on the entrance of site Ⅱ at the binding phase Ⅲ (16.5 ns (a), 17.3 ns (b), and 18 ns (c)) Hydrogen bonds are in yellow (color online).
Fig 8 Comparison on the binding modes of ibuprofen on site Ⅱ of HSA (a) simulation at 30 ns; (b) crystal structure of 2BXG. Same key polar residues are in blue and same hydrophobic residues in orange. The different top-10 residues are in pink. color online
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