Modeling of Platinum-Aryl Interaction with Amyloid-β Peptide

Abstract

Ligand field molecular mechanics (LFMM), density functional theory (DFT) and semi-empirical PM7 methods are used to study the binding of two Pt(II)-L systems to an N-terminal fragment of the amyloid-β peptide, where L = 2,2-bipyridyl or 1,10-phenanthroline. Molecular dynamics simulations are used to explore the conformational freedom of the peptide using LFMM combined with AMBER molecular mechanics parameters. We establish a modelling protocol, allowing for identification and analysis of favorable platinum-binding modes and peptide conformations.Preferred binding modes are identified for each ligand investigated; metal coordination occurs via Nε in His residues for both ligands -His6ε-His13ε and His6ε-His14ε for the bipyridyl and phenanthroline ligands, respectively. The observed change in binding mode for the different ligands suggests that the binding mode of these platinum-based structures can be controlled by the choice of ligand. In the bipy systems, Boltzmann population at 310K is dominated by a single conformer, while in the phenanthroline case, three conformations make significant contributions 2 to the ensemble. The relative stability of these conformations is due to the inherent stability of binding platinum via Nε in addition to subtle H-bonding effects.

Prediction of ligand effects in platinum-amyloid-β coordination

“…During the LMMD search, the platinum centre was set at a fixed potential to avoid premature termination of the conformational search. 31 Semi-empirical calculations were performed using the Molecular Orbital PACkage (MOPAC) in its 2012 39 version, with the Parametric Model 7 (PM7) method 40 and the Conductor-like Screening Model (COSMO) model of aqueous solvation 41 . Overlay plots and images were obtained using Chimera imaging software 42 .…”

“…This gives δFεε 'the flexibility and generality of quantum mechanics with the speed of molecular mechanics.' 23 which has allowed success in the modelling of a range of Jahn-Teller active Cu II systems 27 , spin states of Ni and Fe complexes 28 as well as some Pt II -biomolecule studies 29,30,31 .…”

Ligand field molecular dynamics simulation of Pt(II)-phenanthroline binding to N-terminal fragment of amyloid-β peptide

“…[ 20 ][ 21 ] In addition, Streltsov et al used a combination of EXAFS and DFT to probe local binding environment at Pt and derive structural models for the interaction of platinum complexes with Aβ16 and Aβ42. [ 22 ] Recently, we showed that ligand field molecular mechanics (LFMM) [ 23 ][ 24 ][ 25 ] is an appropriate method to probe the binding of Pt to fragments of Aβ, characterising the effect of Pt complexes on limiting conformational freedom of the peptide [ 26 ] and the role of ligand variation in complexes formed and 3D conformation adopted. [ 27 ] In this work, we extend this approach to examine the dynamical behaviour of a typical Pt-Aβ adduct using molecular dynamics simulations and LFMM description of metal coordination coupled with conventional molecular mechanics (MM) for the peptide.…”

Replica exchange molecular dynamics simulation of the coordination of Pt(ii)-Phenanthroline to amyloid-β

“…Streltsov et al 29 used a combination of EXAFS and density functional theory (DFT) to conrm binding through His residues, while our group has used DFT, semi-empirical and molecular mechanics methods to examine Pt binding to model peptides. [30][31][32] The intrinsically disordered nature of Ab means that such studies struggle to sample the full conformational exibility of the peptide. To address this possible shortcoming, and to provide further details of possible Pt(phen)-peptide interactions and the effect of metal coordination on peptide structure at a molecular level, we performed replica-exchange molecular dynamics (REMD) simulations of the platinum complex interacting with both the Nterminal Ab16 fragment and complete Ab42 peptides.…”