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Protein Sci. 2015 Apr;24(4):474-83. doi: 10.1002/pro.2592. Epub 2014 Nov 5.

Vibrational entropy differences between mesophile and thermophile proteins and their use in protein engineering.

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Department of Biochemistry, Faculty of Medicine and Health Sciences, University of Sherbrooke, J1H 5N4, Quebec, Canada.


We recently introduced ENCoM, an elastic network atomic contact model, as the first coarse-grained normal mode analysis method that accounts for the nature of amino acids and can predict the effect of mutations on thermostability based on changes vibrational entropy. In this proof-of-concept article, we use pairs of mesophile and thermophile homolog proteins with identical structures to determine if a measure of vibrational entropy based on normal mode analysis can discriminate thermophile from mesophile proteins. We observe that in around 60% of cases, thermophile proteins are more rigid at equivalent temperatures than their mesophile counterpart and this difference can guide the design of proteins to increase their thermostability through series of mutations. We observe that mutations separating thermophile proteins from their mesophile orthologs contribute independently to a decrease in vibrational entropy and discuss the application and implications of this methodology to protein engineering.


flexibility; mesophiles; normal mode analysis; protein engineering; thermophiles; thermostability; vibrational entropy

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