ABSTRACT The interest in finding the keys to thermal stabilization of proteins is unquestionable. The approximations, both theoretical and experimental to the problem of thermal stabilizing proteins to date are reviewed. Empirical approximations, using directed mutagenesis have started with the principle that Nature has thermostabilized proteins punctually and opportunistically in each particular case, solving each specific problem in each specific situation. Although the comparison of mesophilic and thermophilic sequences has suggested some thermostabilization mechanisms, it has not been able ‘per se’ to allow for unambiguous thermostabilization rules to every case. The problem associated is precisely the difficulty in proposing simple rules to enhance the thermostability of a given protein based on the experience from other proteins, with the further aggravation that in the majority of cases negative thermostabilizations are seldom reported. Careful analysis of more than two hundred point mutants leading to enhanced thermostability/thermoresistence permits suggesting some general rules for protein thermal stabilization. The most significant findings during the last four years have been in the role of ion –pair networks, in the packing of hydrophobic core, and in the elongating of proteins, as well as in new examples of other established effects.
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