Acta Phys. -Chim. Sin. ›› 2012, Vol. 28 ›› Issue (11): 2735-2744.doi: 10.3866/PKU.WHXB201207162

• BIOPHYSICAL CHEMISTRY • Previous Articles     Next Articles

Molecular Dynamics Simulation and Binding Free Energy Calculation of the Conformational Transition of Amyloid Peptide 42 Inhibited by Peptide Inhibitors

DONG Xiao-Yan, DU Wen-Jie, LIU Fu-Feng   

  1. Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P. R. China; Key Laboratory of Systems Bioengineering, Ministry of Education, Tianjin University, Tianjin 300072, P. R. China
  • Received:2012-05-14 Revised:2012-07-16 Published:2012-10-17
  • Supported by:

    The project was supported by the National Natural Science Foundation of China (20906068, 21076149), National Key Basic Research Program of China (973) (2009CB724705), and Natural Science Foundation of Tianjin from Tianjin Municipal Science and Technology Commission, China (10JCYBJC04500).


The molecular mechanisms of the conformational transition of amyloid β-peptide (Aβ) 42 inhibited by the peptide inhibitors KLVFF, VVIA, and LPFFD were studied by using molecular dynamics simulations and binding free energy calculations. These studies confirmed that the conformational transition of Aβ42 from its initial α-helix to β-sheet structure is prevented by these three peptide inhibitors. The calculations also demonstrated that the intra-peptide hydrophobic interactions of Aβ42 are weakened, and its quantity of long range contacts decreased by these inhibitors. Consequently, the hydrophobic collapse of Aβ42 is alleviated and its initial structure is maintained well. Both hydrophobic and electrostatic interactions, including hydrogen bonding, were found to favor the binding of these peptide inhibitors to Aβ42. Moreover, the charged residues of the inhibitors were shown to enhance the electrostatic interactions including hydrogen bonding, decreasing the capacity of the peptide for self-assembly, and increasing the inhibition effect. It was also determined that interactions between the inhibitors and Aβ42 are reduced when proline residue is introduced into the peptide inhibitor, since its linear structure is disrupted. In general, this work has allowed a better understanding of the molecular mechanisms of the effects of the peptide inhibitors KLVFF, VVIA, and LPFFD on the conformational transition of Aβ42 and will assist in the systematic design of high efficiency peptide inhibitors of Aβ aggregation.

Key words: Molecular dynamics simulation, Alzheimer’s disease, Amyloid peptide, Peptide inhibitor, Conformational transition


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