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Biophys J. 2008 Nov 1;95(9):4139-47. doi: 10.1529/biophysj.108.132407. Epub 2008 Jul 25.

Conformational changes of alpha-chymotrypsin in a fibrillation-promoting condition: a molecular dynamics study.

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Institute of Biochemistry and Biophysics, Department of Cell and Molecular Biology, Faculty of Science, University of Tehran, Tehran, Iran.


Amyloid nanofibril formation appears to be a generic property of polypeptide chains. alpha-Chymotrypsin (aCT) was recently driven toward amyloid-like aggregation by the addition of trifluoroethanol (TFE) at intermediate concentrations. In this study we employed a molecular dynamics simulation to investigate the early events in TFE-induced conformational changes of aCT that precede amyloid formation, and compared the results of the simulation with previous experiments. TFE molecules were found to rapidly replace the water molecules closely associated with the protein surface. The gyration radius, together with total and hydrophobic solvent-accessible surface areas of aCT, was significantly increased. In accord with the experimental observations, the extended beta-conformation of backbone was increased. The secondary structural elements of aCT in water and TFE/water mixture showed a reasonable fit, whereas significant deviations were observed for several loops. These alterations originated largely from main-chain rotations at glycine residues. The catalytic active site and S1 binding pocket of the enzyme were also distorted in the TFE/water mixture. The obtained results are suggested to provide more insights into the conformational properties of the amyloid aggregation-prone protein species. Possible mechanisms of TFE-induced alterations in the conformation and dynamics of the protein structure are also discussed.

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