Intrinsic basis of thermostability of prolyl oligopeptidase

Salt-bridges play a key role in the thermostability of proteins adapted in stress environments whose intrinsic basis remains to be understood. We find that the higher hydrophilicity of PfP than that of HuP is due to the charged but not the polar residues. The primary role of these residues is to enhance the salt-bridges and their ME. Unlike HuP, PfP has made many changes in its intrinsic property to strengthen the salt-bridge. First, the desolvation energy is reduced by directing the salt-bridge towards the surface. Second, it has made bridge-energy more favorable by recruiting energetically advantageous partners with high helix-propensity among the six possible salt-bridge pairs. Third, ME-residues that perform intricate interactions have increased their energy contribution by making major changes in their binary properties.

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Fig: PfP has higher hydrophilicity due to the higher abundance of salt-bridge forming residues (SBFR). Hydrophilicity profiles (a) and grand average hydrophilicity (b) of PfP (black) and HuP (grey). Normalized relative abundance (RApr in %) of salt-bridge forming residues (charged), hydrophobic, and polar classes of amino acids (c) of the sequence of PfP in reference to HuP. Normalized relative abundance (in %) of salt-bridge forming residues for isolated pair (d) and network unit (e) types of salt-bridges of PfP in reference to HuP. The normalized relative abundance of pair-types of salt-bridge for isolated-pair (f) and network unit (g) of PfP in reference to HuP.

The use of salt-bridge partners as ME-residues, and ME-residues’ overlapping usage, predominant in helices, and energetically favorable substitution are some of the favorable features of PfP compared to HuP. These changes in PfP reduce the unfavorable, increase the favorable ME-energy. Thus, the per salt-bridge stability of PfP is greater than that of HuP. Further, unfavorable target ME-residues can be identified whose mutation can increase the stability of salt-bridge. The study applies to other similar systems.

Banerjee, S., Gupta, P.S.S., Islam, R.N.U. et al. Intrinsic basis of thermostability of prolyl oligopeptidase from Pyrococcus furiosus. Sci Rep 11, 11553 (2021). https://doi.org/10.1038/s41598-021-90723-4

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