Protein Engineering, Vol. 13, No. 3, 179-191,
March 2000
© 2000 Oxford University Press
Factors enhancing protein thermostability
1 Intramural Research Support Program, SAIC Frederick, 2 Laboratory of Experimental and Computational Biology, National Cancer Institute, Frederick Cancer Research and Development Center, Bldg 469, Rm 151, Frederick, MD 21702, USA and 3 Sackler Institute of Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
Several sequence and structural factors have been proposed to contribute toward greater stability of thermophilic proteins. Here we present a statistical examination of structural and sequence parameters in representatives of 18 non-redundant families of thermophilic and mesophilic proteins. Our aim was to look for systematic differences among thermophilic and mesophilic proteins across the families. We observe that both thermophilic and mesophilic proteins have similar hydrophobicities, compactness, oligomeric states, polar and non-polar contribution to surface areas, main-chain and side-chain hydrogen bonds. Insertions/deletions and proline substitutions do not show consistent trends between the thermophilic and mesophilic members of the families. On the other hand, salt bridges and side chain–side chain hydrogen bonds increase in the majority of the thermophilic proteins. Additionally, comparisons of the sequences of the thermophile–mesophile homologous protein pairs indicate that Arg and Tyr are significantly more frequent, while Cys and Ser are less frequent in thermophilic proteins. Thermophiles both have a larger fraction of their residues in the 
-helical conformation, and they avoid Pro in their -helices to a greater extent than the mesophiles. These results indicate that thermostable proteins adapt dual strategies to withstand high temperatures. Our intention has been to explore factors contributing to the stability of proteins from thermophiles with respect to the melting temperatures (Tm), the best descriptor of thermal stability. Unfortunately, Tm values are available only for a few proteins in our high resolution dataset. Currently, this limits our ability to examine correlations in a meaningful way.
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