We combine experimental and theoretical methods to assess the effect of a set of point mutations on c7A, a highly mechanostable type I cohesin module from scaffoldin CipA from Clostridium thermocellum. We propose a novel robust and computationally expedient theoretical method to determine the effects of point mutations on protein structure and stability. We use all-atom simulations to predict structural shifts with respect to the native protein and then analyze the mutants using a coarse-grained model. We examine transitions in contacts between residues and find that changes in the contact map usually involve a non-local component that can extend up to 50 Å. We have identified mutations that may lead to a substantial increase in mechanical and thermodynamic stabilities by making systematic substitutions into alanine and phenylalanine in c7A. Experimental measurements of the mechanical stability and circular dichroism data agree qualitatively with the predictions provided the thermal stability is calculated using only the contacts within the secondary structures.
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Non-local effects of point mutations on the stability of a protein module
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14 September 2017
Research Article|
September 08 2017
Non-local effects of point mutations on the stability of a protein module
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JCP Editors' Choice 2017
Mateusz Chwastyk;
Mateusz Chwastyk
a)
1
Institute of Physics, Polish Academy of Sciences
, Al. Lotników 32/46, PL-02668 Warsaw, Poland
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Andrés M. Vera;
Andrés M. Vera
2
Instituto Cajal, Consejo Superior de Investigaciones Científicas, (CSIC)
, Ave. Doctor Arce, 37, 28002 Madrid, Spain
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Albert Galera-Prat;
Albert Galera-Prat
2
Instituto Cajal, Consejo Superior de Investigaciones Científicas, (CSIC)
, Ave. Doctor Arce, 37, 28002 Madrid, Spain
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Melissabye Gunnoo;
Melissabye Gunnoo
3
Department of Physics, Bernal Institute, University of Limerick
, Limerick V94 T9PX, Ireland
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Damien Thompson;
Damien Thompson
3
Department of Physics, Bernal Institute, University of Limerick
, Limerick V94 T9PX, Ireland
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Mariano Carrión-Vázquez;
Mariano Carrión-Vázquez
2
Instituto Cajal, Consejo Superior de Investigaciones Científicas, (CSIC)
, Ave. Doctor Arce, 37, 28002 Madrid, Spain
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Marek Cieplak
Marek Cieplak
b)
1
Institute of Physics, Polish Academy of Sciences
, Al. Lotników 32/46, PL-02668 Warsaw, Poland
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a)
Current address: Department of Physics, Arizona State University, Tempe, Arizona 85287, USA.
b)
Electronic mail: mc@ifpan.edu.pl
J. Chem. Phys. 147, 105101 (2017)
Article history
Received:
April 15 2017
Accepted:
July 30 2017
Citation
Mateusz Chwastyk, Andrés M. Vera, Albert Galera-Prat, Melissabye Gunnoo, Damien Thompson, Mariano Carrión-Vázquez, Marek Cieplak; Non-local effects of point mutations on the stability of a protein module. J. Chem. Phys. 14 September 2017; 147 (10): 105101. https://doi.org/10.1063/1.4999703
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