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Biochim Biophys Acta. 2013 May;1834(5):854-66. doi: 10.1016/j.bbapap.2013.02.011. Epub 2013 Feb 14.

Stability and rigidity/flexibility-two sides of the same coin?

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Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.


Protein molecules require both flexibility and rigidity for functioning. The fast and accurate prediction of protein rigidity/flexibility is one of the important problems in protein science. We have determined flexible regions for four homologous pairs from thermophilic and mesophilic organisms by two methods: the fast FoldUnfold which uses amino acid sequence and the time consuming MDFirst which uses three-dimensional structures. We demonstrate that both methods allow determining flexible regions in protein structure. For three of the four thermophile-mesophile pairs of proteins, FoldUnfold predicts practically the same flexible regions which have been found by the MD/First method. As expected, molecular dynamics simulations show that thermophilic proteins are more rigid in comparison to their mesophilic homologues. Analysis of rigid clusters and their decomposition provides new insights into protein stability. It has been found that the local networks of salt bridges and hydrogen bonds in thermophiles render their structure more stable with respect to fluctuations of individual contacts. Such network includes salt bridge triads Agr-Glu-Lys and Arg-Glu-Arg, or salt bridges (such as Arg-Glu) connected with hydrogen bonds. This ionic network connects alpha helices and rigidifies the structure. Mesophiles can be characterized by stand alone salt bridges and hydrogen bonds or small ionic clusters. Such difference in the network of salt bridges results in different flexibility of homologous proteins. Combining both approaches allows characterizing structural features in atomic detail that determine the rigidity/flexibility of a protein structure. This article is a part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.

[Indexed for MEDLINE]

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