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

The molecular mechanisms of the conformational transition of amyloid beta-peptide (A beta) 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 A beta 42 from its initial alpha-helix to beta-sheet structure is prevented by these three peptide inhibitors. The calculations also demonstrated that the intra-peptide hydrophobic interactions of A beta 42 are weakened, and its quantity of long range contacts decreased by these inhibitors. Consequently, the hydrophobic collapse of A beta 42 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 A beta 42. 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 A beta 42 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 A beta 42 and will assist in the systematic design of high efficiency peptide inhibitors of A beta aggregation.