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Protein Engineering vol. 8 no. 1 pp. 21-30, 1995
© 1995 Oxford University Press

RESEARCH-ARTICLE

Increasing thermal stability of subtilisin from mutations suggested by strongly interacting side-chain clusters

Jaap Heringa1,2, Patrick Argos1, Maarten R. Egmond3 and Jacob de Vlieg3

1European Molecular Biology Laboratory (EMBL) Meyerhofstraße 1, Postfach 10.2209, D-69012 Heidelberg, Germany 3Unilever Research Laboratory Olivier van Noortlaan 120, 3133 AT Vlaardingen, The Netherlands

2To whom correspondence should be addressed

In this paper we present for seven subtilisin structures a systematic comparison of densely packed side-group clusters (defined as an ensemble of side chains with extensive internal atomic contacts as compared with those made with the surrounding protein environment and measured relative to the maximum possible for each residue type). Spatially consistent clusters are observed at structurally equivalent positions in the proteins, as revealed by careful multiple superpositioning of the respective backbone atoms. The clusters are positioned at strategic loop-connecting sites near the protein surfaces. The residues within consistent clusters displaying extensive association show varying conservation at structurally equivalent alignment sites. Suggestions for residue substitutions, as observed over the seven tertiary structures, were taken from the cluster positions and were shown to be consistent with a number of point mutations in one of the seven structures (savinase) that result in increased thermal stability.

Keywords: local unfolding/protein thermostability/side-chain clusters/site-directed mutagenesis/stability nucleation sites/subtilisin

Received May 31, 1994; revised October 7, 1994; accepted November 7, 1994.


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