STRUCTURAL DISTRIBUTION OF DIPEPTIDES THAT ARE IDENTIFIED TO BE DETERMINANTS OF INTRACELLULAR PROTEIN STABILITY

The dipeptides that had been previously implicated as determinants of in vivo protein stability (Guruprasad, K., Reddy, B. V. B. and Pandit, M. W., 1990. Protein Eng. 4, 155 - 161) have been reassessed on a lat est data set and about 25% dipeptide combinations (102 dipeptides) wer e found to play significant role in determining the intracellular prot ein stability. These were classified as stabilizing dipeptides (Stb), destabilizing dipeptides (Dst) and normal dipeptides (Nor). By differe nt theoretical approaches we have investigated the global localization of these dipeptides in a set of 303 best resolved (less than or equal to 2.0 Angstrom) non-homologous X-ray defined protein structures. The Dst dipeptides are found to be more of hydrophilic combinations where as Stb dipeptides are more of hydrophobic combinations. We observed a significant difference in overall frequency of occurrence of Stb and Dsr dipeptides in different secondary structural regions. The sensitiv e dipepides (Stb + Dst) are less in beta-strands and more in coils. A high frequency of occurrence of Stb are observed in the regions closer to the molecular surface compared to the Dst and Nor dipeptides. A si gnificantly high dipole interactions are observed in the Dst dipeptide s. The studies indicate that though the Dst dipeptides are more of hyd rophilic nature they are localized significantly more in the buried re gions of protein structures, on the other hand Stb are more of hydroph obic nature but relatively more accessible to the-solvent. These dipep tides therefore increasing sensitivity of the protein to external envi ronment, any alteration in their occurrence in the sequence could incr ease or decrease intracellular stability of the protein. These observa tions are useful to select mutations to alter intracellular stability of a given protein and therefore have implications in protein engineer ing.