Volume 397, Issue 5, 16 April 2010, Pages 1329-1338
Protein Folding Requires Crowd Control in a Simulated Cell
[Sponsored Article]
Benjamin R. Jefferys, a, , Lawrence A. Kelleya, and Michael J.E. Sternberga,
a Division of Molecular Biosciences, Biochemistry Building, Imperial College London, South Kensington, London SW7 2AZ, UK
Received 25 September 2009;
revised 30 December 2009;
accepted 2 January 2010.
Edited by D. Case.
Available online 10 February 2010.
Abstract
Macromolecular crowding has a profound effect upon biochemical processes in the cell. We have computationally studied the effect of crowding upon protein folding for 12 small domains in a simulated cell using a coarse-grained protein model, which is based upon Langevin dynamics, designed to unify the often disjoint goals of protein folding simulation and structure prediction. The model can make predictions of native conformation with accuracy comparable with that of the best current template-free models. It is fast enough to enable a more extensive analysis of crowding than previously attempted, studying several proteins at many crowding levels and further random repetitions designed to more closely approximate the ensemble of conformations. We found that when crowding approaches 40% excluded volume, the maximum level found in the cell, proteins fold to fewer native-like states. Notably, when crowding is increased beyond this level, there is a sudden failure of protein folding: proteins fix upon a structure more quickly and become trapped in extended conformations. These results suggest that the ability of small protein domains to fold without the help of chaperones may be an important factor in limiting the degree of macromolecular crowding in the cell. Here, we discuss the possible implications regarding the relationship between protein expression level, protein size, chaperone activity and aggregation.
Keywords: macromolecular crowding; protein structure prediction; protein misfolding; protein aggregation; protein expression
Abbreviations: TM, template modelling
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[Sponsored Article]
Benjamin R. Jefferys, a, , Lawrence A. Kelleya, and Michael J.E. Sternberga,
a Division of Molecular Biosciences, Biochemistry Building, Imperial College London, South Kensington, London SW7 2AZ, UK
Received 25 September 2009;
revised 30 December 2009;
accepted 2 January 2010.
Edited by D. Case.
Available online 10 February 2010.
Abstract
Macromolecular crowding has a profound effect upon biochemical processes in the cell. We have computationally studied the effect of crowding upon protein folding for 12 small domains in a simulated cell using a coarse-grained protein model, which is based upon Langevin dynamics, designed to unify the often disjoint goals of protein folding simulation and structure prediction. The model can make predictions of native conformation with accuracy comparable with that of the best current template-free models. It is fast enough to enable a more extensive analysis of crowding than previously attempted, studying several proteins at many crowding levels and further random repetitions designed to more closely approximate the ensemble of conformations. We found that when crowding approaches 40% excluded volume, the maximum level found in the cell, proteins fold to fewer native-like states. Notably, when crowding is increased beyond this level, there is a sudden failure of protein folding: proteins fix upon a structure more quickly and become trapped in extended conformations. These results suggest that the ability of small protein domains to fold without the help of chaperones may be an important factor in limiting the degree of macromolecular crowding in the cell. Here, we discuss the possible implications regarding the relationship between protein expression level, protein size, chaperone activity and aggregation.
Keywords: macromolecular crowding; protein structure prediction; protein misfolding; protein aggregation; protein expression
Abbreviations: TM, template modelling
+++++
FREE PDF GRÁTIS
+++++
Vote neste blog para o prêmio TOPBLOG 2010.
