Amino acid composition and thermal stability of protein structures: the free energy geography of the Protein Data Bank

TL;DR

This study analyzes how amino acid composition and chain length influence protein thermal stability, revealing that hydrogen bonds and hydrophobic effects are key factors, with different stability patterns across protein groups.

Contribution

Introduces a new internal free energy parameterization revealing the thermal stability landscape of proteins in the PDB based on amino acid composition and chain length.

Findings

Most proteins have internal free energy between -2 and -6.5 kJ/mol/res.

Hydrogen bonds significantly stabilize DPR proteins.

Long DPR proteins are absent due to hydrophobicity and de-hydration energy constraints.

Abstract

We study the combined influence of amino acid composition and chain length on the thermal stability of protein structures. A new parameterization of the internal free energy is considered, as the sum of hydrophobic effect, hydrogen-bond and de-hydration energy terms. We divided a non-redundant selection of protein structures from the Protein Data Bank into three groups: i) rich in order-promoting residues (OPR proteins); ii) rich in disorder-promoting residues (DPR proteins); iii) belonging to a twilight zone (TZ proteins). We observe a partition of PDB in several groups with different internal free energies, amino acid compositions and protein lengths. Internal free energy of 96% of the proteins analyzed ranges from -2 to -6.5 kJ/mol/res. We found many DPR and OPR proteins with the same relative thermal stability. Only OPR proteins with internal energy between -4 and -6.5 kJ/mol/res are observed to have chains longer than 200 residues, with a high de-hydration energy compensated by the hydrophobic effect. DPR and TZ proteins are shorter than 200 residues and they have an internal energy above -4 kJ/mol/res, with a few exceptions among TZ proteins. Hydrogen-bonds play an important role in the stabilization of these DPR folds, often higher than contact energy. The new parameterization of internal free energy let emerge a geography of thermal stabilities of PDB structures. Amino acid composition per se is not sufficient to determine the stability of protein folds, since. DPR and TZ proteins generally have a relatively high internal free energy, and they are stabilized by hydrogen-bonds. Long DPR proteins are not observed in the PDB, because their low hydrophobicity cannot compensate the high de-hydration energy necessary to accommodate residues within a highly packed globular fold.