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      Coarse Master Equations for Binding Kinetics of Amyloid Peptide Dimers

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          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 to discriminate 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.

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          Author and article information

          Journal
          The Journal of Physical Chemistry Letters
          J. Phys. Chem. Lett.
          American Chemical Society (ACS)
          1948-7185
          June 30 2016
          July 21 2016
          June 30 2016
          July 21 2016
          : 7
          : 14
          : 2676-2682
          Affiliations
          [1 ]School of Physics, University College Dublin, Belfield, Dublin 4, Ireland
          [2 ]Complex and Adaptive Systems Laboratory, University College Dublin, Belfield, Dublin 4, Ireland
          [3 ]Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max-von-Laue-Straße 3, D-60438 Frankfurt am Main, Germany
          [4 ]Department of Chemistry, King’s College London, London SE1 1DB, United Kingdom
          Article
          10.1021/acs.jpclett.6b00518
          27323250
          269b79f3-2c6b-47fe-94a3-f679de6a66ef
          © 2016

          http://pubs.acs.org/page/policy/authorchoice_termsofuse.html

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