Polarization effect of zinc on the region 1-16 of amyloid-beta peptide: a molecular dynamics study

TL;DR

This study uses molecular dynamics simulations to investigate how zinc influences the structure and aggregation of amyloid-beta peptide region 1-16, highlighting the role of polarization effects in zinc-peptide interactions relevant to Alzheimer's disease.

Contribution

The paper introduces a novel all-atom molecular dynamics model incorporating polarization effects to accurately simulate zinc binding to amyloid-beta peptide region 1-16.

Findings

Proper van der Waals parameters are crucial for realistic zinc coordination.

Induced polarization promotes stabilization and solvent exposure of residues.

The model reproduces experimentally observed zinc binding configurations.

Abstract

Zinc is found saturated in the deposited Amyloid-beta (AB) peptide plaques in brains of patients subjected to Alzheimer disease (AD). Zinc binding to AB promotes aggregations, including the toxic soluble AB species. Up to now, only the region 1-16 of AB complexed with Zinc (AB16-Zn) is defined structurally in experiment, requiring an efficient theoretical method to present the interaction between zinc and AB peptide. In order to explore the induced polarization effect on the global conformation fluctuations and the experimentally observed coordination mode of AB16-Zn, in this work we consider an all-atom molecular dynamics (MD) of AB16-Zn solvated in implicit water. In our model the polarization effect affects the whole peptide is applied. The induced dipoles are divided into three distinct scales according to their distances from zinc. Besides, the atomistic polarizability on the coordinating sidechains is rescaled to describe the electron redistribution effect. As a comparison, another model which exactly follows the method of Sakharov and Lim (J. Am. Chem. Soc., 127, 13, 2005) has been discussed also. We show that, associated with proper van der Waals (vdW) parameters, our model not only obtains the reasonable coordinating configuration of zinc binding site, but also retains the global stabilization, especially the N-terminal region, of the AB16-Zn. We suggest that it is the induced polarization effect that promotes reasonable solvent exposures of hydrophobic/hydrophilic residues regarding zinc-induced AB aggregation.