Forcefield evaluation and accelerated molecular dynamics simulation of Zn(II) binding to N-terminus of amyloid-β

Alshammari, Nadiyah, Savva, Loizos, Kennedy-Britten, Oliver and Platts, James A. ORCID: https://orcid.org/0000-0002-1008-6595 2021. Forcefield evaluation and accelerated molecular dynamics simulation of Zn(II) binding to N-terminus of amyloid-β. Computational Biology and Chemistry 93 , 107540. 10.1016/j.compbiolchem.2021.107540

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Abstract

We report conventional and accelerated molecular dynamics simulation of Zn(II) bound to the N-terminus of amyloid-β. By comparison against NMR data for the experimentally determined binding mode, we find that certain combinations of forcefield and solvent model perform acceptably in describing the size, shape and secondary structure, and that there is no appreciable difference between implicit and explicit solvent models. We therefore used the combination of ff14SB forcefield and GBSA solvent model to compare the result of different binding modes of Zn(II) to the same peptide, using accelerated MD to enhance sampling and comparing the free peptide simulated in the same way. We show that Zn(II) imparts significant rigidity to the peptide, disrupts the secondary structure and pattern of salt bridges seen in the free peptide, and induces closer contact between residues. Free energy surfaces in 1 or 2 dimensions further highlight the effect of metal coordination on peptide’s spatial extent. We also provide evidence that accelerated MD provides improved sampling over conventional MD by visiting as many or more configurations in much shorter simulation times.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Chemistry
Publisher:	Elsevier
ISSN:	1476-9271
Date of First Compliant Deposit:	14 July 2021
Date of Acceptance:	21 June 2021
Last Modified:	06 Nov 2023 15:50
URI:	https://orca.cardiff.ac.uk/id/eprint/142579

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