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2014, Volume 8, Issue 4

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Frontiers of Chemical Science and Engineering >> 2014, Volume 8, Issue 4 doi: 10.1007/s11705-014-1454-6

Atomistic characterization of binding modes and affinity of peptide inhibitors to amyloid-

1. Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.2. Department of Chemical and Biomolecular Engineering, The University of Akron, Akron, OH 44325, USA.3. Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China

Accepted: 2014-12-30 Available online: 2015-01-14
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Abstract

The aggregation of amyloid -protein (A ) 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 aggregation and alleviate A -induced neurotoxicity. However, atomic details of binding modes and binding affinities between these peptide inhibitors and A 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 and the molecular basis of their inhibition. All inhibitors exhibit varied binding affinity to A , 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 , consequently hotspot binding residues, and underlying driving forces. Specific residue-based interactions between inhibitors and A 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 aggregation.

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