DETERMINATION OF ATOMIC DESOLVATION ENERGIES FROM THE STRUCTURES OF CRYSTALLIZED PROTEINS

We estimated effective atomic contact energies (ACE), the desolvation free energies required to transfer atoms from water to a protein's int erior, using an adaptation of a method introduced by S. Miyazawa and R . L. Jernigan. The energies were obtained for 18 different atom types, which were resolved on the basis of the way their properties cluster in the 20 common amino acids. In addition to providing information on atoms at the highest resolution compatible with the amount and quality of data currently available, the method itself has several new featur es, including its reference state, the random crystal structure, which removes compositional bias, and a scaling factor that makes contact e nergies quantitatively comparable with experimentally measured energie s. The high level of resolution, the explicit accounting of the local properties of protein interiors during determination of the energies, and the very high computational efficiency with which they can be assi gned during any computation, should make the results presented here wi dely applicable. First we used ACE to calculate the free energies of t ransferring side-chains from protein interior into water. A comparison of the results thus obtained with the measured free energies of trans ferring side-chains from n-octanol to water, indicates that the magnit ude of protein to water transfer free energies for hydrophobic side-ch ains is larger than that of n-octanol to water transfer free energies. The difference is consistent with observations made by D. Shortie and co-workers, who measured differential free energies of protein unfold ing for site-specific mutants in which Ala or Gly was substituted for various hydrophobic side-chains. A direct comparison (calculated versu s observed free energy differences) with those experiments finds slope s of 1.15 and 1.13 for Gly and Ala substitutions, respectively. Finall y we compared calculated and observed binding free energies of nine pr otease-inhibitor complexes. This requires a full free energy function, which is created by adding direct electrostatic interactions and an a ppropriate entropic component to the solvation free energy term. The c alculated free energies are typically within 10% of the observed value s. Taken collectively, these results suggest that ACE should provide a reasonably accurate and rapidly evaluatable solvation component of fr ee energy, and should thus make accessible a range of docking, design and protein folding calculations that would otherwise be difficult to perform. (C) 1997 Academic Press Limited.