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Li M.S.,Polish Academy of Sciences | Co N.T.,Saigon Institute for Computational Science and Technology | Reddy G.,University of Maryland University College | Hu C.-K.,Academia Sinica, Taiwan | And 3 more authors.
Physical Review Letters | Year: 2010

Using lattice models we explore the factors that determine the tendencies of polypeptide chains to aggregate by exhaustively sampling the sequence and conformational space. The morphologies of the fibril-like structures and the time scales (τfib) for their formation depend on a balance between hydrophobic and Coulomb interactions. The extent of population of an ensemble of N⊃* structures, which are fibril-prone structures in the spectrum of conformations of an isolated protein, is the major determinant of τfib. This observation is used to determine the aggregating sequences by exhaustively exploring the sequence space, thus providing a basis for genome wide search of fragments that are aggregation prone. © 2010 The American Physical Society.

Co N.T.,Saigon Institute for Computational Science and Technology | Li M.S.,Polish Academy of Sciences
Journal of Chemical Physics | Year: 2012

A new method for determining the size of critical nucleus of fibril formation of polypeptide chains is proposed. Based on the hypothesis that the fibril grows by addition of a nascent peptide to the preformed template, the nucleus size N c is defined as the number of forming template peptides above which the time to add a new monomer becomes independent of the template size. Using lattice models one can show that our method and the standard method which is based on calculation of the free energy, provide the same result for N c. © 2012 American Institute of Physics.

Arad-Haase G.,Weizmann Institute of Science | Chuartzman S.G.,Weizmann Institute of Science | Dagan S.,Weizmann Institute of Science | Nevo R.,Weizmann Institute of Science | And 5 more authors.
Biophysical Journal | Year: 2010

Single-molecule manipulation methods provide a powerful means to study protein transitions. Here we combined single-molecule force spectroscopy and steered molecular-dynamics simulations to study the mechanical properties and unfolding behavior of the small enzyme acylphosphatase (AcP). We find that mechanical unfolding of AcP occurs at relatively low forces in an all-or-none fashion and is decelerated in the presence of a ligand, as observed in solution measurements. The prominent energy barrier for the transition is separated from the native state by a distance that is unusually long for α/β proteins. Unfolding is initiated at the C-terminal strand (βT) that lies at one edge of the β-sheet of AcP, followed by unraveling of the strand located at the other. The central strand of the sheet and the two helices in the protein unfold last. Ligand binding counteracts unfolding by stabilizing contacts between an arginine residue (Arg-23) and the catalytic loop, as well as with βT of AcP, which renders the force-bearing units of the protein resistant to force. This stabilizing effect may also account for the decelerated unfolding of ligand-bound AcP in the absence of force. © 2010 by the Biophysical Society.

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