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Coarse Master Equations for Binding Kinetics of Amyloid Peptide Dimers
Date Issued
2016-07
Date Available
2018-01-23T18:09:47Z
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.
Sponsorship
Irish Research Council
Other Sponsorship
The Engineering and Physical Sciences Research Council (EPSRC)
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
Language
English
Status of Item
Peer reviewed
This item is made available under a Creative Commons License
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