Folding, misfolding and amyloid protofibril formation of WW domain FBP28

¹ Nanyang Technological University
² School of Biological Sciences, NTU

^* To whom correspondence should be addressed. E-mail: ygmu{at}ntu.edu.sg.

Submitted on October 19, 2005
Revised on January 15, 2006
Accepted on 28 February 2006

	Abstract

We study the folding mechanism of a triple- strand WW domain from the Formin binding protein 28 (FBP28) at atomic resolution with explicit water model using replica exchange molecular dynamics computer simulations. Extended sampling over a wide range of temperatures to obtain the free energy, enthalpy and entropy surfaces as a function of structural coordinates has been performed. Simulations were started from different configurations covering the folded and unfolded states. In the free energy landscape a transition state is identified and its structures and -values are compared with experimental data from a homologous protein, the prolyl-isomerase Pin1 WW domain. A stable intermediate state is found to accumulate during the simulation characterized by the carboxyl-terminal -strand 3 having misregistered hydrogen bonds and where the structural heterogeneity is due to nonnative turn II formation. Furthermore, the aggregation behavior of the FBP28 WW domain may be related to one such misfolded structure, which has a much lower free energy of dimer formation than that of the native dimer. Based on the misfolded dimer, aggregation to form protofibril structure is discussed.

Key Words: amyloid fibril, energy landscape, molecular dynamics simulation, replica exchange, transition states, turn formation propensity

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