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.
We study two-state protein folding in the framework of a toy model of protein dynamics. This model has an important advantage: it allows for an analytical solution for the sum of folding and unfolding rate constants [A. M. Berezhkovskii, F. Tofoleanu, and N.-V. Buchete, J. Chem. Theory Comput. 7, 2370 (2011)10.1021/ct200281d] and hence for the reactive flux at equilibrium. We use the model to test the Kramers-type formula for the reactive flux, which was derived assuming that the protein dynamics is described by a Markov random walk on a network of complex connectivity [A. Berezhkovskii, G. Hummer, and A. Szabo, J. Chem. Phys. 130, 205102 (2009)10.1063/1.3139063]. It is shown that the Kramers-type formula leads to the same result for the reactive flux as the sum of the rate constants.
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