Coarse Master Equations for Binding Kinetics of Amyloid Peptide Dimers

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Title: Coarse Master Equations for Binding Kinetics of Amyloid Peptide Dimers
Authors: Leahy, Cathal
Murphy, Ronan D.
Hummer, Gerhard
Rosta, Edina
Buchete, Nicolae-Viorel
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Date: Jul-2016
Abstract: We characterize the kinetics of dimer formation of the short amyloid microcrystal-forming tetrapeptides NNQQ by constructing coarse master equations for the conformational dynamics of the system, using temperature replica-exchange molecular dynamics (REMD) simulations. We minimize the effects of Kramers-type recrossings by assigning conformational states based on their sequential time evolution. Transition rates are further estimated from short-time state propagators, by maximizing the likelihood that the extracted rates agree with the observed atomistic trajectories without any a priori assumptions about their temperature dependence. Here, we evaluate the rates for both continuous replica trajectories that visit different temperatures, and for discontinuous data corresponding to each REMD temperature. While the binding-unbinding kinetic process is clearly Markovian, the conformational dynamics of the bound NNQQ dimer has a complex character. Our kinetic analysis allows us a quantitative discrimination between short-lived encounter pairs and strongly bound conformational states. The conformational dynamics of NNQQ dimers supports a kinetically driven aggregation mechanism, in agreement with the polymorphic character reported for amyloid aggregates such as microcrystals and fibrils.
Funding Details: Irish Research Council
Type of material: Journal Article
Publisher: ACS
Journal: Journal of Physical Chemistry Letters
Volume: 7
Issue: 14
Start page: 2676
End page: 2682
Copyright (published version): 2017 American Chemical Society
Keywords: Replica-exchange molecular dynamicsDimer formation
DOI: 10.1021/acs.jpclett.6b00518
Language: en
Status of Item: Peer reviewed
Appears in Collections:Physics Research Collection
CASL Research Collection

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