Electromagnetic-field effects on structure and dynamics of amyloidogenic peptides Nevena Todorova, Alan Bentvelzen, Niall J. English, and Irene Yarovsky
Citation: J. Chem. Phys. 144, 085101 (2016); doi: 10.1063/1.4941108 View online: http://dx.doi.org/10.1063/1.4941108 View Table of Contents: http://aip.scitation.org/toc/jcp/144/8 Published by the American Institute of Physics
,
THE JOURNAL OF CHEMICAL PHYSICS 144, 085101 (2016)
Electromagnetic-field effects on structure and dynamics of amyloidogenic peptides Nevena Todorova,1,2 Alan Bentvelzen,1,2 Niall J. English,3 and Irene Yarovsky1,2,a) 1
School of Engineering, RMIT University, G.P.O. Box 2476, Melbourne, Australia NH&MRC Australian Centre for Electromagnetic Bioeffects Research, Australia 3 School of Chemical & Bioprocess Engineering, University College Dublin, Belfield, Dublin 4, Ireland
2
(Received 17 November 2015; accepted 20 January 2016; published online 23 February 2016) Electromagnetic fields (EMFs) are ever-present, and so is the need to better understand their influence on human health and biological matter in general. The interaction between a molecular system and external EMF can alter the structure, and dynamical behaviour, and, hence, biological function of proteins with uncertain health consequences. This urges a detailed investigation of EMF-induced effects on basic protein biophysics. Here, we used all-atom non-equilibrium molecular dynamics simulations to understand and quantify the response mechanisms of the amyloidogenic apoC-II(60-70) peptides to non-ionising radiation by modelling their behaviour under external electromagnetic and electric fields of different strengths. Our simulations show high strength fields (>0.04 V/nm) cause structural changes in apoC-II(60-70) due to the peptide dipole alignment along the applied field direction, which disrupts the inherent β-hairpin conformation known to be the intermediate state for fibril formation. The intermediate field-strength range (0.04-0.004 V/nm) causes a significant acceleration in peptide dynamics, which leads to the increased population of structures with fibril-inhibiting characteristics, such as the separated N- and C-termini and colocation of the aromatic residues at the same peptide face. In contrast, lower field strengths (0.3 V/nm) induced elongation of the peptide conformation, where both EMF and EF simulations sampled similar regions on the FEM with ∼3.5 nm average N-C terminal distance separation and ∼1.09 nm average Rg. In the medium-strength field range (0.04-0.07 V/nm), we observed
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diverse conformations, which provide the transitional pathway between the elongated (high-field) and compact (low-field) peptide states. Here, we also observe some differences between the EMF- and EF-sampled structures. Specifically, the EF simulations exhibit a broader transition pathway between the two low energy states, indicating external EFs of 0.04-0.07 V/nm strength induce significant structural dynamics in the apoC-II(60-70) peptide, preventing it from stabilising in a particular conformation, as evidenced by the large number of clusters obtained in our cluster analysis (vide supra). The broad landscape sampled for these field strengths, together with the contributions of individual simulations to the overall FEM, is shown in the supplementary material.41 In contrast, the EMF simulations exhibited narrower transitional pathways, confirming our initial observation that the applied EMF was able to stabilise, or trap, certain conformations of the peptide. This is demonstrated here by the highly populated cluster (37%) observed in the 0.07 V/nm EMF containing structures with average N-C terminal separation of 1.86 ± 0.15 nm, compared to EF simulations where the most significant cluster had only 15% and structures with terminal separations of 0.64 ± 0.13 nm. The distinct structural preference induced by the 0.07 V/nm EMF simulations is demonstrated by the presence of two “hot spots” along the transition pathway (∼3 nm N-C distance/∼0.97 nm Rg and ∼1.8 nm N-C distance/∼0.61 nm Rg, cf. the supplementary material).41 At the low field strengths (0.3 V/nm) showed structures with a broad distribution of the angles between the aromatic pairs, as expected due to the elongated conformations sampled at this level of exposure. The 0.07 V/nm trajectories showed peptide preference for angles between the aromatic rings of less than 90◦, with peaks seen at 30◦ and 50◦ for the EMF and EF simulations, respectively. This suggests that apoC-II(60-70) adopts fibril-inhibiting structures at this “intermediate” field range strength. As the applied field strength approaches the lower field range, there is an evident shift in the aromatic-angle orientation preference to the opposite peptide faces. The results for the most populated cluster showed that in the EMF and EF of
Citation: J. Chem. Phys. 144, 085101 (2016); doi: 10.1063/1.4941108 View online: http://dx.doi.org/10.1063/1.4941108 View Table of Contents: http://aip.scitation.org/toc/jcp/144/8 Published by the American Institute of Physics
,
THE JOURNAL OF CHEMICAL PHYSICS 144, 085101 (2016)
Electromagnetic-field effects on structure and dynamics of amyloidogenic peptides Nevena Todorova,1,2 Alan Bentvelzen,1,2 Niall J. English,3 and Irene Yarovsky1,2,a) 1
School of Engineering, RMIT University, G.P.O. Box 2476, Melbourne, Australia NH&MRC Australian Centre for Electromagnetic Bioeffects Research, Australia 3 School of Chemical & Bioprocess Engineering, University College Dublin, Belfield, Dublin 4, Ireland
2
(Received 17 November 2015; accepted 20 January 2016; published online 23 February 2016) Electromagnetic fields (EMFs) are ever-present, and so is the need to better understand their influence on human health and biological matter in general. The interaction between a molecular system and external EMF can alter the structure, and dynamical behaviour, and, hence, biological function of proteins with uncertain health consequences. This urges a detailed investigation of EMF-induced effects on basic protein biophysics. Here, we used all-atom non-equilibrium molecular dynamics simulations to understand and quantify the response mechanisms of the amyloidogenic apoC-II(60-70) peptides to non-ionising radiation by modelling their behaviour under external electromagnetic and electric fields of different strengths. Our simulations show high strength fields (>0.04 V/nm) cause structural changes in apoC-II(60-70) due to the peptide dipole alignment along the applied field direction, which disrupts the inherent β-hairpin conformation known to be the intermediate state for fibril formation. The intermediate field-strength range (0.04-0.004 V/nm) causes a significant acceleration in peptide dynamics, which leads to the increased population of structures with fibril-inhibiting characteristics, such as the separated N- and C-termini and colocation of the aromatic residues at the same peptide face. In contrast, lower field strengths (0.3 V/nm) induced elongation of the peptide conformation, where both EMF and EF simulations sampled similar regions on the FEM with ∼3.5 nm average N-C terminal distance separation and ∼1.09 nm average Rg. In the medium-strength field range (0.04-0.07 V/nm), we observed
085101-5
Todorova et al.
diverse conformations, which provide the transitional pathway between the elongated (high-field) and compact (low-field) peptide states. Here, we also observe some differences between the EMF- and EF-sampled structures. Specifically, the EF simulations exhibit a broader transition pathway between the two low energy states, indicating external EFs of 0.04-0.07 V/nm strength induce significant structural dynamics in the apoC-II(60-70) peptide, preventing it from stabilising in a particular conformation, as evidenced by the large number of clusters obtained in our cluster analysis (vide supra). The broad landscape sampled for these field strengths, together with the contributions of individual simulations to the overall FEM, is shown in the supplementary material.41 In contrast, the EMF simulations exhibited narrower transitional pathways, confirming our initial observation that the applied EMF was able to stabilise, or trap, certain conformations of the peptide. This is demonstrated here by the highly populated cluster (37%) observed in the 0.07 V/nm EMF containing structures with average N-C terminal separation of 1.86 ± 0.15 nm, compared to EF simulations where the most significant cluster had only 15% and structures with terminal separations of 0.64 ± 0.13 nm. The distinct structural preference induced by the 0.07 V/nm EMF simulations is demonstrated by the presence of two “hot spots” along the transition pathway (∼3 nm N-C distance/∼0.97 nm Rg and ∼1.8 nm N-C distance/∼0.61 nm Rg, cf. the supplementary material).41 At the low field strengths (0.3 V/nm) showed structures with a broad distribution of the angles between the aromatic pairs, as expected due to the elongated conformations sampled at this level of exposure. The 0.07 V/nm trajectories showed peptide preference for angles between the aromatic rings of less than 90◦, with peaks seen at 30◦ and 50◦ for the EMF and EF simulations, respectively. This suggests that apoC-II(60-70) adopts fibril-inhibiting structures at this “intermediate” field range strength. As the applied field strength approaches the lower field range, there is an evident shift in the aromatic-angle orientation preference to the opposite peptide faces. The results for the most populated cluster showed that in the EMF and EF of
