Title

Atomistic Characterization of Binding Modes and Affinity of Peptide Inhibitors to Amyloid-beta Protein

Document Type

Article

Publication Date

Winter 12-2014

Abstract

The aggregation of amyloid beta-protein (A beta) is tightly linked to the pathogenesis of Alzheimer's disease. Previous studies have found that three peptide inhibitors (i.e., KLVFF, VVIA, and LPFFD) can inhibit A beta aggregation and alleviate A beta-induced neurotoxicity. However, atomic details of binding modes and binding affinities between these peptide inhibitors and A beta have not been revealed. Here, using molecular dynamics simulations and molecular mechanics Poisson Boltzmann surface area (MM/PBSA) analysis, we examined the effect of three peptide inhibitors (KLVFF, VVIA, and LPFFD) on their sequence-specific interactions with A beta and the molecular basis of their inhibition. All inhibitors exhibit varied binding affinity to A beta, in which KLVFF has the highest binding affinity, whereas LPFFD has the least. MM/PBSA analysis further revealed that different peptide inhibitors have different modes of interaction with A beta, consequently hotspot binding residues, and underlying driving forces. Specific residue-based interactions between inhibitors and A beta were determined and compared for illustrating different binding and inhibition mechanisms. This work provides structure-based binding information for further modification and optimization of these three peptide inhibitors to enhance their binding and inhibitory abilities against A beta aggregation.

Publication Title

Frontiers of Chemical Science and Engineering

Volume

8

Issue

4

First Page

433

Last Page

444

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